Search results for: clinical predictions

Authors: Nadjet Mekaouche, Hanane Zitouni, Fatma Boudia, Habiba Fetati, A. Saleh, A. Lardjam, H. Geniaux, A. Coubret, H. Toumi

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Medicines have undeniably played a major role in prolonging shelf life and improving quality. The absolute efficacy of the drug remains a lever for innovation, its benefit/risk balance is not always assured and it does not always have the expected effects. Prior to marketing, knowledge about adverse drug reactions is incomplete. Once on the market, phase IV drug studies begin. For years, the drug was prescribed with less care to a large number of very heterogeneous patients and often in combination with other drugs. It is at this point that previously unknown adverse effects may appear, hence the need for the implementation of a pharmacovigilance system. Pharmacovigilance represents all methods for detecting, evaluating, informing and preventing the risks of adverse drug reactions. The most severe adverse events occur frequently in hospital and that a significant proportion of adverse events result in hospitalizations. In addition, the consequences of hospital adverse events in terms of length of stay, mortality and costs are considerable. It, therefore, appears necessary to develop ‘hospital pharmacovigilance’ aimed at reducing the incidence of adverse reactions in hospitals. The most widely used monitoring method in pharmacovigilance is spontaneous notification. However, underreporting of adverse drug reactions is common in many countries and is a major obstacle to pharmacovigilance assessment. It is in this context that this study aims to describe the experience of the pharmacovigilance service at the University Hospital of Oran (EHUO). This is a retrospective study extending from 2011 to 2017, carried out on archived records of declarations collected at the level of the EHUO Pharmacovigilance Department. Reporting was collected by two methods: ‘spontaneous notification’ and ‘active pharmacovigilance’ targeting certain clinical services. We counted 217 statements. It involved 56% female patients and 46% male patients. Age ranged from 5 to 78 years with an average of 46 years. The most common adverse reaction was drug toxidermy. For the drugs in question, they were essentially according to the ATC classification of anti-infectives followed by anticancer drugs. As regards the evolution of declarations by year, a low rate of notification was noted in 2011. That is why we decided to set up an active approach at the level of some services where a resident of reference attended the staffs every week. This has resulted in an increase in the number of reports. The declarations came essentially from the services where the active approach was installed. This highlights the need for ongoing communication between all relevant health actors to stimulate reporting and secure drug treatments.

Keywords: adverse drug reactions, hospital, pharmacovigilance, spontaneous notification

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Authors: Pedro Batista, André Vinha, Filipe Castelo, Bárbara Costa, Ricardo Sousa, Raquel Ricardo, André Pinto

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Background: Septic arthritis is a diagnosis that must be considered in any patient presenting with acute joint swelling and fever. Among the several risk factors for septic arthritis, such as age, rheumatoid arthritis, recent surgery, or skin infection, diabetes mellitus can sometimes be the main risk factor. Staphylococcus aureus is the most common pathogen isolated in septic arthritis; however, it is uncommon in monomicrobial necrotizing fasciitis. Objectives: A case report of concomitant septic arthritis and necrotizing fasciitis in a patient with undiagnosed diabetes based on clinical history. Study Design & Methods: We report a case of a 58-year-old Portuguese previously healthy man who presented to the emergency department with fever and left knee swelling and pain for two days. The blood work revealed ketonemia of 6.7 mmol/L and glycemia of 496 mg/dL. The vital signs were significant for a temperature of 38.5 ºC and 123 bpm of heart rate. The left knee had edema and inflammatory signs. Computed tomography of the left knee showed diffuse edema of the subcutaneous cellular tissue and soft tissue air bubbles. A diagnosis of septic arthritis and necrotising fasciitis was made. He was taken to the operating room for surgical debridement. The samples collected intraoperatively were sent for microbiological analysis, revealing infection by multi-sensitive Staphylococcus aureus. Given this result, the empiric flucloxacillin (500 mg IV) and clindamycin (1000 mg IV) were maintained for 3 weeks. On the seventh day of hospitalization, there was a significant improvement in subcutaneous and musculoskeletal tissues. After two weeks of hospitalization, there was no purulent content and partial closure of the wounds was possible. After 3 weeks, he was switched to oral antibiotics (flucloxacillin 500 mg). A week later, a urinary infection by Pseudomonas aeruginosa was diagnosed and ciprofloxacin 500 mg was administered for 7 days without complications. After 30 days of hospital admission, the patient was discharged home and recovered. Results: The final diagnosis of concomitant septic arthritis and necrotizing fasciitis was made based on the imaging findings, surgical exploration and microbiological tests results. Conclusions: Early antibiotic administration and surgical debridement are key in the management of septic arthritis and necrotizing fasciitis. Furthermore, risk factors control (euglycemic blood glucose levels) must always be taken into account given the crucial role in the patient's recovery.

Keywords: septic arthritis, Necrotizing fasciitis, diabetes, Staphylococcus Aureus

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Authors: Ling-Ling E., Hong-Chen Liu, Dong-Sheng Wang, Fang Su, Xia Wu, Zhan-Ping Shi, Yan Lv, Jia-Zhu Wang

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Objective: The objective of the present study is to evaluate the capacity of a tissue-engineered bone complex of recombinant human bone morphogenetic protein 2 (rhBMP-2) mediated dental pulp stem cells (DPSCs) and nano-hydroxyapatite/collagen/poly(L-lactide)(nHAC/PLA) to reconstruct critical-size alveolar bone defects in New Zealand rabbit. Methods: Autologous DPSCs were isolated from rabbit dental pulp tissue and expanded ex vivo to enrich DPSCs numbers, and then their attachment and differentiation capability were evaluated when cultured on the culture plate or nHAC/PLA. The alveolar bone defects were treated with nHAC/PLA, nHAC/PLA+rhBMP-2, nHAC/PLA+DPSCs, nHAC/PLA+DPSCs+rhBMP-2, and autogenous bone (AB) obtained from iliac bone or were left untreated as a control. X-ray and a polychrome sequential fluorescent labeling were performed post-operatively and the animals were sacrificed 12 weeks after operation for histological observation and histomorphometric analysis. Results: Our results showed that DPSCs expressed STRO-1 and vementin, and favoured osteogenesis and adipogenesis in conditioned media. DPSCs attached and spread well, and retained their osteogenic phenotypes on nHAC/PLA. The rhBMP-2 could significantly increase protein content, alkaline phosphatase (ALP) activity/protein, osteocalcin (OCN) content, and mineral formation of DPSCs cultured on nHAC/PLA. The X-ray graph, the fluorescent, histological observation and histomorphometric analysis showed that the nHAC/PLA+DPSCs+rhBMP-2 tissue-engineered bone complex had an earlier mineralization and more bone formation inside the scaffold than nHAC/PLA, nHAC/PLA+rhBMP-2 and nHAC/PLA+DPSCs, or even autologous bone. Implanted DPSCs contribution to new bone were detected through transfected eGFP genes. Conclutions: Our findings indicated that stem cells existed in adult rabbit dental pulp tissue. The rhBMP-2 promoted osteogenic capability of DPSCs as a potential cell source for periodontal bone regeneration. The nHAC/PLA could serve as a good scaffold for autologous DPSCs seeding, proliferation and differentiation. The tissue-engineered bone complex with nHAC/PLA, rhBMP-2, and autologous DPSCs might be a better alternative to autologous bone for the clinical reconstruction of periodontal bone defects.

Keywords: nano-hydroxyapatite/collagen/poly (L-lactide), dental pulp stem cell, recombinant human bone morphogenetic protein, bone tissue engineering, alveolar bone

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Authors: Janice Keener, Christine Houlihan

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Over the last several years, there has been an increase in children identified as having Autism Spectrum Disorder (ASD). Specialists across several disciplines: mental health and medical professionals have been tasked with ensuring accurate and timely evaluations for children with suspected ASD. Due to the nature of the ASD symptom presentation, an interdisciplinary assessment and treatment approach best addresses the needs of the whole child. During the unprecedented COVID-19 Pandemic, clinicians were faced with how to continue with interdisciplinary assessments in a telehealth arena. Instruments that were previously used to assess ASD in-person were no longer appropriate measures to use due to the safety restrictions. For example, The Autism Diagnostic Observation Schedule requires examiners and children to be in very close proximity of each other and if masks or face shields are worn, they render the evaluation invalid. Similar issues arose with the various cognitive measures that are used to assess children such as the Weschler Tests of Intelligence and the Differential Ability Scale. Thus the need arose to identify measures that are able to be safely and accurately administered using safety guidelines. The incidence of ASD continues to rise over time. Currently, the Center for Disease Control estimates that 1 in 59 children meet the criteria for a diagnosis of ASD. The reasons for this increase are likely multifold, including changes in diagnostic criteria, public awareness of the condition, and other environmental and genetic factors. The rise in the incidence of ASD has led to a greater need for diagnostic and treatment services across the United States. The uncertainty of the diagnostic process can lead to an increased level of stress for families of children with suspected ASD. Along with this increase, there is a need for diagnostic clarity to avoid both under and over-identification of this condition. Interdisciplinary assessment is ideal for children with suspected ASD, as it allows for an assessment of the whole child over the course of time and across multiple settings. Clinicians such as Psychologists and Developmental Pediatricians play important roles in the initial evaluation of autism spectrum disorder. An ASD assessment may consist of several types of measures such as standardized checklists, structured interviews, and direct assessments such as the ADOS-2 are just a few examples. With the advent of telehealth clinicians were asked to continue to provide meaningful interdisciplinary assessments via an electronic platform and, in a sense, going to the family home and evaluating the clinical symptom presentation remotely and confidently making an accurate diagnosis. This poster presentation will review the benefits, limitations, and interpretation of these various instruments. The role of other medical professionals will also be addressed, including medical providers, speech pathology, and occupational therapy.

Keywords: Autism Spectrum Disorder Assessments, Interdisciplinary Evaluations , Tele-Assessment with Autism Spectrum Disorder, Diagnosis of Autism Spectrum Disorder

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Authors: Priyanka Bhowmik, Subrata Majumdar, Debprasad Chattopadhyay

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Background: Cervical cancer is the third major cause of cancer in women and the second most frequent cause of cancer related deaths causing 300,000 deaths annually worldwide. Evasion of immune response by Human Papilloma Virus (HPV), the key contributing factor behind cancer and pre-cancerous lesions of the uterine cervix, makes immunotherapy a necessity to treat this disease. Objective: A Heat killed fraction of Mycobacterium indicus pranii (MIP), a non-pathogenic Mycobacterium has been shown to exhibit cytotoxic effects on different cancer cells, including human cervical carcinoma cell line HeLa. However, the underlying mechanisms remain unknown. The aim of this study is to decipher the mechanism of MIP induced HeLa cell death. Methods: The cytotoxicity of Mycobacterium indicus pranii against HeLa cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by annexin V and Propidium iodide (PI) staining. The assessment of reactive oxygen species (ROS) generation and cell cycle analysis were measured by flow cytometry. The expression of apoptosis associated genes was analyzed by real time PCR. Result: MIP could inhibit the proliferation of HeLa cell in a time and dose dependent manner but caused minor damage to normal cells. The induction of apoptosis was confirmed by the cell surface presentation of phosphatidyl serine, DNA fragmentation, and mitochondrial damage. MIP caused very early (as early as 30 minutes) transcriptional activation of p53, followed by a higher activation (32 fold) at 24 hours suggesting prime importance of p53 in MIP-induced apoptosis in HeLa cell. The up regulation of p53 dependent pro-apoptotic genes Bax, Bak, PUMA, and Noxa followed a lag phase that was required for the transcriptional p53 program. MIP also caused the transcriptional up regulation of Toll like receptor 2 and 4 after 30 minutes of MIP treatment suggesting recognition of MIP by toll like receptors. Moreover, MIP caused the inhibition of expression of HPV anti apoptotic gene E6, which is known to interfere with p53/PUMA/Bax apoptotic cascade. This inhibition might have played a role in transcriptional up regulation of PUMA and subsequently apoptosis. ROS was generated transiently which was concomitant with the highest transcription activation of p53 suggesting a plausible feedback loop network of p53 and ROS in the apoptosis of HeLa cells. Scavenger of ROS, such as N-acetyl-L-cysteine, decreased apoptosis suggesting ROS is an important effector of MIP induced apoptosis. Conclusion: Taken together, MIP possesses full potential to be a novel therapeutic agent in the clinical treatment of cervical cancer.

Keywords: cancer, mycobacterium, immunity, immunotherapy.

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Authors: Rashmi Shukla, Yamini Bhusan Tripathi

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Diabetic nephropathy (DN) is characterized as diabetic kidney disease which involves many pathways e.g. hyperactivated protein kinase c (PKC), polyol pathway, excess production of advanced glycation end product (AGEs) & free radical accumulation etc. All of them results to hypoxia followed by apoptosis of podocytes, glomerulosclerosis, extracellular matrix (ECM) accumulation and fibrosis resulting to irreversible changes in kidney. This is continuously rising worldwide and there are not enough specific drugs, to retard its progress. Due to increasing side effects of allopathic drugs, interest in herbal remedies is growing. Earlier, we have reported that PTY-2 (a phytomedicine, derived from Pueraria tuberosa Linn.) inhibits the accumulation of extracellular matrix (ECM) through activation of MMP-9. Present study exhibited the therapeutic potential of Pueraria tuberosa in the prevention of podocytes apoptosis and modulation of nephrin expression in streptozotocin (STZ) induced DN rats. DN rats were produced by maintaining persistent hyperglycemia for 8 weeks by intra-peritoneal injection of 55 mg/kg streptozotocin (STZ). These rats were randomly divided in 2 groups, i.e. DN control, and DN+ water extract of Pueraria tuberosa (PTW). One group of age-matched normal rats served as non-diabetic control (group-1), The STZ induced DN rats (group-2) and DN+PTW treated rats (group-3). The PTW was orally administered (0.3g/kg) daily to group-2 rats and drug vector (1 ml of 10% tween 20) in control rats. The treatments were continued for 20 days and blood and urine samples were collected. Rats were then sacrificed to investigate the expression Bcl2, Bax and nephroprotective protein i.e. nephrin in kidney glomerulus. The effect of PTW was evaluated, we have found that the PTW significantly(p < .001) reversed the raised serum urea, serum creatinine, urine protein and improved the creatinine clearance in STZ induce diabetic nephropathy in rats and also significantly(p < .001) prevented the rise in urine albumin excretion. The Western blot analysis of kidney tissue homogenate showed increased expression of Bcl2 in PTW treated rats. The RT-PCR showed the increased expression and accumulation of nephrin mRNA. The confocal photomicrographs also supported the reduction of Bax and a simultaneous increase in Bcl2 and nephrin in glomerular podocytes. Hence, our finding suggests that the nephroprotective role of PTW is mediated via restoration of nephrin thus prevents the podocytes apoptosis and ameliorates diabetic nephropathy. The clinical trial of PTW would prove to be a potential food supplement/ drug of alternative medicine for patients with diabetic nephropathy in early stage.

Keywords: Pueraria tuberosa, diabetic nephropathy, anti-apoptosis, nephrin

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Authors: Bijad Alqahtani, Graham Arnold, Weijie Wang

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Background—Tai Chi Chuan (TCC) is a type of traditional Chinese martial art and is considered a benefiting physical fitness. Advanced techniques of motion analysis have been routinely used in the clinical assessment. However, so far, little research has been done on the biomechanical assessment of TCC players in terms of gait and balance using motion analysis. Objectives—The aim of this study was to investigate whether TCC improves the lower limb conditions and balance ability using the state of the art motion analysis technologies, i.e. motion capture system, electromyography and force platform. Methods—Twenty TCC (9 male, 11 female) with age between (42-77) years old and weight (56.2-119 Kg), and eighteen Non-TCC participants (7 male, 11 female), weight (50-110 Kg) with age (43- 78) years old at the matched age as a control group were recruited in this study. Their gait and balance were collected using Vicon Nexus® to obtain the gait parameters, and kinematic parameters of hip, knee, and ankle joints in three planes of both limbs. Participants stood on force platforms to perform a single leg balance test. Then, they were asked to walk along a 10 m walkway at their comfortable speed. Participants performed 5 trials of single-leg balance for the dominant side. Also, the participants performed 3 trials of four square step balance and 10 trials of walking. From the recorded trials, three good ones were analyzed using the Vicon Plug-in-Gait model to obtain gait parameters, e.g. walking speed, cadence, stride length, and joint parameters, e.g. joint angle, force, moments, etc. Result— The temporal-spatial variables of TCC subjects were compared with the Non-TCC subjects, it was found that there was a significant difference (p < 0.05) between the groups. Moreover, it was observed that participants of TCC have significant differences in ankle, hip, and knee joints’ kinematics in the sagittal, coronal, and transverse planes such as ankle angle (19.90±19.54 deg) for TCC while (15.34±6.50 deg) for Non-TCC, and knee angle (14.96±6.40 deg) for TCC while (17.63±5.79 deg) for Non-TCC in the transverse plane. Also, the result showed that there was a significant difference between groups in the single-leg balance test, e.g. maintaining single leg stance time in the TCC participants showed longer duration (20.85±10.53 s) in compared to Non-TCC people group (13.39±8.78 s). While the result showed that there was no significant difference between groups in the four square step balance. Conclusion—Our result showed that there are significant differences between Tai Chi Chuan and Non-Tai Chi Chuan participants in the various aspects of gait analysis and balance test, as a consequence of these findings some of biomechanical parameters such as joints kinematics, gait parameters and single leg stance balance test, the Tai Chi Chuan could improve the lower limb conditions and could reduce a risk of fall for the elderly with ageing.

Keywords: gait analysis, kinematics, single leg stance, Tai Chi Chuan

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Authors: Showkat Ahmad Bhat, Iqra Reyaz, Falaque ul Afshan, Ahmad Arif Reshi, Muneeb U. Rehman, Manzoor R. Mir, Sabhiya Majid, Sonallah, Sheikh Bilal, Ishraq Hussain

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Background: Gastric cancer is the fourth most common cancer and the second leading cause of worldwide cancer-related deaths, with a wide variation in incidence rates across different geographical areas. The current view of cancer is that a malignancy arises from a transformation of the genetic material of a normal cell, followed by successive mutations and by chain of alterations in genes such as DNA repair genes, oncogenes, Tumor suppressor genes. Minerals are necessary for the functioning of several transcriptional factors, proteins that recognize certain DNA sequences and have been found to play a role in gastric cancer. Material Methods:The present work was a case control study and its aim was to ascertain the role of minerals and promoter hypermethylation of CpG islands of DAP-K gene in Gastric cancer patients among the Kashmiri population. Serum was extracted from all the samples and mineral estimation was done by AAS from serum, DNA was also extracted and was modified using bisulphite modification kit. Methylation-specific PCR was used for the analysis of the promoter hypermethylation status of DAP-K gene. The epigenetic analysis revealed that unlike other high risk regions, Kashmiri population has a different promoter hypermethylation profile of DAP-K gene and has different mineral profile. Results: In our study mean serum copper levels were significantly different for the two genders (p<0.05), while as no significant differences were observed for iron and zinc levels. In Methylation-specific PCR the methylation status of the promoter region of DAP-K gene was as 67.50% (27/40) of the gastric cancer tissues showed methylated DAP-K promoter and 32.50% (13/40) of the cases however showed unmethylated DAP-K promoter. Almost all 85% (17/20) of the histopathologically confirmed normal tissues showed unmethylated DAP-K promoter except only in 3 cases where DAP-K promoter was found to be methylated. The association of promoter hypermethylation with gastric cancer was evaluated by χ2 (Chi square) test and was found to be significant (P=0.0006). Occurrence of DAP-K methylation was found to be unequally distributed in males and females with more frequency in males than in females but the difference was not statistically significant (P =0.7635, Odds ratio=1.368 and 95% C.I=0.4197 to 4.456). When the frequency of DAP-K promoter methylation was compared with clinical staging of the disease, DAP-K promoter methylation was found to be certainly higher in Stage III/IV (85.71%) compared to Stage I/ II (57.69%) but the difference was not statistically significant (P =0.0673). These results suggest that DAP-K aberrant promoter hypermethylation in Kashmiri population contributes to the process of carcinogenesis in Gastric cancer and is reportedly one of the commonest epigenetic changes in the development of Gastric cancer.

Keywords: gastric cancer, minerals, AAS, hypermethylation, CpG islands, DAP-K gene

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Authors: Sinem Bulkan

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This study introduces the construct of psychopathic manager behaviour and aims for the development of psychopathic manager behaviour (Psycho-Man B) measure. The study also aims for the understanding of the relationship between psychopathic manager behaviour and workplace deviance while investigating the mediating role of a revenge motive and the moderating roles of the core self-evaluations and the attitude importance. Data were collected from 519 employees from a wide variety of jobs and industries who currently work for or previously worked for a manager in a collectivist culture, Turkey. Psycho-Man B Measure was developed resulting in five dimensions as opposed to the proposed ten dimensions. Simple linear and hierarchical regression analyses were conducted to test the hypotheses. The results of simple linear regression analyses showed that psychopathic manager behaviour was positively significantly related to supervisor-directed and organisation-directed deviance. Revenge motive towards the manager partially mediated the relationship between psychopathic manager behaviour and supervisor-directed deviance. Similarly, revenge motive towards the organisation partially mediated the relationship between psychopathic manager behaviour and organisation-directed deviance. Furthermore, no support was found for the expected moderating role of core self-evaluations in the revenge motive towards the manager-supervisor-directed deviance and revenge motive towards the organisation-organisation-directed deviance relationships. Attitude importance moderated the relationship between revenge motive towards the manager and supervisor-directed deviance; revenge motive towards the organisation and organisation-directed deviance. Moderated-mediation hypotheses were not supported for core self-evaluations but were supported for the attitude importance. Additional analyses for sub-dimensions were conducted to further examine the hypotheses. Demographic variables were examined through independent samples t-tests, and one way ANOVA. Finally, findings are discussed; limitations, suggestions and implications are presented. The major contribution of this study is that ‘psychopathic manager behaviour’ construct was introduced to the literature and a scale for the reliable identification of psychopathic manager behaviour was developed in to evaluate managers’ level of sub-clinical psychopathy in the workforce. The study introduced that employees engage in different forms of supervisor-directed deviance and organisation-directed deviance depending on the level of the emotions and personal goals. Supervisor-directed deviant behaviours and organisation-directed deviant behaviours became distinct in a way as impulsive and premeditated, active or passive, direct and indirect actions. Accordingly, it is important for organisations to notice that employees’ level of affective state and attitude importance for psychopathic manager behaviours predetermine the certain type of employee deviant behaviours.

Keywords: attitude importance, core self evaluations, psychopathic manager behaviour, revenge motive, workplace deviance

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Authors: Zohre Shahhosseini, Mehdi Pourasghar, AliReza Khalilian, Fariba Salehi

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Objective: The prevalence of anxiety during pregnancy, particularly in developing countries, and its adverse effects on mother and baby, can make pregnancy unpleasant for pregnant women. The effect of anxiety during pregnancy on birth outcomes and children can be a justification for screening of anxious pregnant women in periodic pregnancy care and helping them. In this study, researchers have investigated effects and comparison of group counseling (Cognitive therapy) and interactive lectures on anxiety during pregnancy of primiparas. Methods: The population studied in this semi-experimental trail was nulliparous pregnant women with backgrounds in health care centers in Sari city .They were studied during a period of 3 months from early March to end May 2016. Sample size in this study was 91 patients, who were randomly assigned to three groups: group counseling, interactive lecture, and control group. Demographic questionnaire and Speilberger State –Trait Anxiety Inventory (SPAI) was completed for all three groups after obtaining letter of consent and completing the initial checklist. Then interventions included 4 sessions for group counseling and 4 sessions for interactive lecture which were implemented in two sessions a week. 4 weeks after interventions, Speilberger State – Trait Anxiety Inventory (SPAI), completed by both group counseling and interactive lectures groups again. In control group, the second questionnaire was also completed 4 weeks after completing the initial questionnaire. Data analysis was performed using spss software version 18. At first, the Kalmogorov-Smiranov test was carried out and then chi square tests, Independent t-test, paired t-test, ANOVA test, and Dunnett's post hoc test were applied. Results: Findings show that group counseling and interactive lecture with reducing state and trait anxiety in significant level of P=0/000 contribute to reduction of anxiety in nulliparous pregnant mothers. However, in this study, group counseling was more effective than an interactive lecture in reducing participants' anxiety, but this difference was not significant (P≥0/05). Conclusions: According to the results of this study, it is suggested that by screening of psychological - mental problems of pregnant women in periodic care during pregnancy be considered by revised prenatal care plans and creation of counseling and training units at health centers. Besides owing to the fact that both interactive lecture and group counseling method were effective in reducing anxiety, these methods should be used proportionate to situations and facilities.

Keywords: anxiety, group counseling, cognitive therapy, interactive lecture, nulliparous

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Authors: Roya Yumul, Chse, Ofelia Loani Elvir Lazo, David Chernobylsky, Omar Durra

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Background: Preoperative anxiety has been shown to be caused by the fear associated with surgical and anesthetic complications; however, the current gold standard for assessing patient anxiety, the STAI, is problematic to use in the preoperative setting given the duration and concentration required to complete the 40-item extensive questionnaire. Our primary aim in the study is to investigate the correlation of the Visual Facial Anxiety Scale (VFAS) and Numerical Verbal Rating Scale (NVRS) to State-Trait Anxiety Inventory (STAI) to determine the optimal anxiety scale to use in the perioperative setting. Methods: A clinical study of patients undergoing various surgeries was conducted utilizing each of the preoperative anxiety scales. Inclusion criteria included patients undergoing elective surgeries, while exclusion criteria included patients with anesthesia contraindications, inability to comprehend instructions, impaired judgement, substance abuse history, and those pregnant or lactating. 293 patients were analyzed in terms of demographics, anxiety scale survey results, and anesthesia data via Spearman Coefficients, Chi-Squared Analysis, and Fischer’s exact test utilized for comparison analysis. Results: Statistical analysis showed that VFAS had a higher correlation to STAI than NVRS (rs=0.66, p<0.0001 vs. rs=0.64, p<0.0001). The combined VFAS-Categorization Scores showed the highest correlation with the gold standard (rs=0.72, p<0.0001). Subgroup analysis showed similar results. STAI evaluation time (247.7 ± 54.81 sec) far exceeds VFAS (7.29 ± 1.61 sec), NVRS (7.23 ± 1.60 sec), and Categorization scales (7.29 ± 1.99 sec). Patients preferred VFAS (54.4%), Categorization (11.6%), and NVRS (8.8%). Anesthesiologists preferred VFAS (63.9%), NVRS (22.1%), and Categorization Scales (14.0%). Of note, the top five causes of preoperative anxiety were determined to be waiting (56.5%), pain (42.5%), family concerns (40.5%), no information about surgery (40.1%), or anesthesia (31.6%). Conclusions: Combined VFAS-Categorization Score (VCS) demonstrates the highest correlation to the gold standard, STAI. Both VFAS and Categorization tests also take significantly less time than STAI, which is critical in the preoperative setting. Among both patients and anesthesiologists, VFAS was the most preferred scale. This forms the basis of the Yumul FACES Anxiety Scale, designed for quick quantization and assessment in the preoperative setting while maintaining a high correlation to the golden standard. Additional studies using the formulated Yumul FACES Anxiety Scale are merited.

Keywords: numerical verbal anxiety scale, preoperative anxiety, state-trait anxiety inventory, visual facial anxiety scale

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Authors: Marcin Jakiel, Maria Kurek, Karolina Gutkowska, Sylwia Sanakiewicz, Dominika Stolarczyk, Jakub Batko, Rafał Jakiel, Mateusz K. Hołda

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Proper imaging of the interventricular septum during endocavital lead implantation is essential for successful procedure. The interventricular septum is located oblique to the 3 main body planes and forms angles of 44.56° ± 7.81°, 45.44° ± 7.81°, 62.49° (IQR 58.84° - 68.39°) with the sagittal, frontal and transverse planes, respectively. The optimal left anterior oblique (LAO) projection is to have the septum aligned along the radiation beam and will be obtained for an angle of 53.24° ± 9,08°, while the best visualization of the septal surface in the right anterior oblique (RAO) projection is obtained by using an angle of 45.44° ± 7.81°. In addition, the RAO angle (p=0.003) and the septal slope to the transverse plane (p=0.002) are larger in the male group, but the LAO angle (p=0.003) and the dihedral angle that the septum forms with the sagittal plane (p=0.003) are smaller, compared to the female group. Analyzing the optimal RAO angle in cross-sections lying at the level of the connections of the septum with the free wall of the right ventricle from the front and back, we obtain slightly smaller angle values, i.e. 41.11° ± 8.51° and 43.94° ± 7.22°, respectively. As the septum is directed leftward in the apical region, the optimal RAO angle for this area decreases (16.49° ± 7,07°) and does not show significant differences between the male and female groups (p=0.23). Within the right ventricular apex, there is a cavity formed by the apical segment of the interventricular septum and the free wall of the right ventricle with a depth of 12.35mm (IQR 11.07mm - 13.51mm). The length of the septum measured in longitudinal section, containing 4 heart cavities, is 73.03mm ± 8.06mm. With the left ventricular septal wall formed by the interventricular septum in the apical region at a length of 10.06mm (IQR 8.86 - 11.07mm) already lies outside the right ventricle. Both mentioned lengths are significantly larger in the male group (p<0.001). For proper imaging of the septum from the right ventricular side, an oblique position of the visualization devices is necessary. Correct determination of the RAO and LAO angle during the procedure allows to improve the procedure performed, and possible modification of the visual field when moving in the anterior, posterior and apical directions of the septum will avoid complications. Overlooking the change in the direction of the interventricular septum in the apical region and a significant decrease in the RAO angle can result in implantation of the lead into the free wall of the right ventricle with less effective pacing and even complications such as wall perforation and cardiac tamponade. The demonstrated gender differences can also be helpful in setting the right projections. A necessary addition to the analysis will be a description of the area of the ventricular septum, which we are currently working on using autopsy material.

Keywords: anatomical variability, angle, electrocardiological procedure, intervetricular septum

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Authors: T. N. Goh, M. Hashmi, O. Hussain

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Temporomandibular joint (TMJ) dysfunction (TMD) is a condition that may affect patients via restricted mouth opening, significant pain during normal functioning, and/or reproducible joint noise. TMD includes myofascial pain, TMJ functional derangements (internal derangement, dislocation), and TMJ degenerative/inflammatory joint disease. Internal derangement (ID) is the most common cause of TMD-related clicking and locking. These patients are managed in a stepwise approach, from patient education (homecare advice and analgesia), splint therapy, physiotherapy, botulinum toxin treatment, to arthrocentesis. Arthrotomy is offered when the aforementioned treatment options fail to alleviate symptoms and improve quality of life. The aim of this prospective study was to review the outcomes of jaw joint open surgery in TMD patients. Patients who presented from 2015-2022 at the Oral and Maxillofacial Surgery Department in the Doncaster NHS Foundation Trust, UK, with a Wilkes classification of III -V were included. These patients underwent either i) discopexy with bone-anchoring suture (9); ii) intrapositional temporalis flap (ITF) with bone-anchoring suture (3); iii) eminoplasty and discopexy with suturing to the capsule (3); iii) discectomy + ITF with bone-anchoring suture (1); iv) discoplasty + bone-anchoring suture (1); v) ITF (1). Maximum incisal opening (MIO) was assessed pre-operatively and at each follow-up. Pain score, determined via the visual analogue scale (VAS, with 0 being no pain and 10 being the worst pain), was also recorded. A total of 18 eligible patients were identified with a mean age of 45 (range 22 - 79), of which 16 were female. The patients were scored by Wilkes Classification as III (14), IV (1), or V (4). Twelve patients had anterior disc displacement without reduction (66%) and six had degenerative/arthritic changes (33%) to the TMJ. The open joint procedure resulted in an increase in MIO and reduction in pain VAS and for the majority of patients, across all Wilkes Classifications. Pre-procedural MIO was 22.9 ± 7.4 mm and VAS was 7.8 ± 1.5. At three months post-procedure there was an increase in MIO to 34.4 ± 10.4 mm (p < 0.01) and a decrease in the VAS to 1.5 ± 2.9 (p < 0.01). Three patients were lost to follow-up prior to six months. Six were discharged at six month review and five patients were discharged at 12 months review as they were asymptomatic with good mouth opening. Four patients are still attending for annual botulinum toxin treatment. Two patients (Wilkes III and V) subsequently underwent TMJ replacement (11%). One of these patients (Wilkes III) had improvement initially to MIO of 40 mm, but subsequently relapsed to less than 20 mm due to lack of compliance with jaw rehabilitation device post-operatively. Clinical improvements in 89% of patients within the study group were found, with a return to near normal MIO range and reduced pain score. Intraoperatively, the operator found bone-anchoring suture used for discopexy/discoplasty more secure than the soft tissue anchoring suturing technique.

Keywords: bone anchoring suture, open temporomandibular joint surgery, temporomandibular joint, temporomandibular joint dysfunction

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Authors: Ying-Jung Hsieh, Angela S. Huang, Chu-Ming Chiu, Yu-Min Chou, Chin-Hui Yang

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Background and Objectives: Hepatitis A is primarily acquired by the fecal-oral route through person-to-person contact or ingestion of contaminated food or water. During 2010 to 2014, an average of 83 cases of locally-acquired disease was reported to Taiwan’s notifiable disease system. Taiwan Centers for Disease Control (TCDC) identified an outbreak of acute hepatitis A which began in June 2015. Of the 126 cases reported in 2015, 103 (82%) cases were reported during June–December and 95 cases (92%) of them were male. The average age of all male cases was 31 years (median, 29 years; range, 15–76 years). Among the 95 male cases, 49 (52%) were also infected with HIV, and all reported to have had sex with other men. To control this outbreak, TCDC launched a free hepatitis A vaccination program in January 2016 for close contacts of confirmed hepatitis A cases, including family members, sexual partners, and household contacts. Effect of the vaccination program was evaluated. Methods: All cases of hepatitis A reported to the National Notifiable Disease Surveillance System were included. A case of hepatitis A was defined as a locally-acquired disease in a person who had acute clinical symptoms include fever, malaise, loss of appetite, nausea or abdominal discomfort compatible with hepatitis, and tested positive for anti-HAV IgM during June 2015 to June 2016 in Taiwan. The rate of case accumulation was calculated using a simple regression model. Results: During January–June 2016, there were 466 cases of hepatitis A reported; of the 243 (52%) who were also infected with HIV, 232 (95%) had a history of having sex with men. Of the 346 cases that were followed up, 259 (75%) provided information on contacts but only 14 (5%) of them provided the name of their sexual partners. Among the 602 contacts reported, 349 (58%) were family members, 14 (2%) were sexual partners, and 239 (40%) were other household contacts. Among the 602 contacts eligible for free hepatitis A vaccination, 440 (73%) received the vaccine. There were 87 (25%) cases that refused to disclose their close contacts. The average case accumulation rate during January–June 2016 was 21.7 cases per month, which was 6.8 times compared to the average case accumulation rate during June–December 2015 of 3.2 cases per month. Conclusions: Despite vaccination program aimed to provide free hepatitis A vaccine to close contacts of hepatitis A patients, the outbreak continued and even gained momentum in transmission. Refusal by hepatitis A patients to provide names of their close contacts and rejection of contacts to take the hepatitis A vaccine may have contributed to the poor effect of the program. Targeted vaccination efforts of all MSM may be needed to control the outbreak among this population in the short term. In the long term, universal vaccination program is needed to prevent the infection of hepatitis A.

Keywords: hepatitis A, HIV, men who have sex with men, vaccination

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Authors: Hanan Bin Nakhi, Asaad M. Albadrawi, Maged Al Shahat, ‎Entesar Mandani

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Background:‎ Kawasaki disease (KD) is one of the most common vasculitis of childhood. ‎It is considered the leading cause of acquired heart disease in children. The ‎peak age of occurrence is 6 to 24 months, with 80% of affected children being ‎less than 5 years old. There are only a few reports of KD in infants younger ‎than 6 months. Infants had a higher incidence of atypical KD and of coronary ‎artery complications. This case report from Kuwait will reinforce considering ‎atypical KD in case of sepsis like condition with negative cultures and ‎unresponding to systemic antibiotics. Early diagnosis allows early treatment ‎with intravenous immune globulin (IVIG) and so decreases the incidence of ‎cardiac aneurysm.‎ Case Report:‎ A 2 month old female infant, product of full term normal delivery to ‎consanguineous parents, presented with fever and poor feeding. She was ‎admitted and treated as urinary tract infection as her urine routine revealed ‎pyurea. The baby continued to have persistent fever and hypoactivity inspite ‎of using intravenous antibiotics. Latter, she developed non purulent ‎conjunctivitis, skin mottling, oedema of the face / lower limb and was treated ‎in intensive care unit as a case of septic shock. In spite of her partial general ‎improvement, she continued to look unwell, hypoactive and had persistent ‎fever. Septic work up, metabolic, and immunologic screen were negative. KD ‎was suspected when the baby developed polymorphic erythematous rash and ‎noticed to have peeling of skin at perianal area and periangular area of the ‎fingers of the hand and feet. IVIG was given in dose of 2 gm/kg/day in single ‎dose and aspirin 100 mg/kg/day in four divided doses. The girl showed marked ‎clinical improvement. The fever subsided dramatically and the level acute ‎phase reactant markedly decreased but the platelets count increased to ‎‎1600000/mm3. Echo cardiography showed mild dilatation of mid right ‎coronary artery. Aspirin was continued in a dose of 5 mg/kg/d till repeating ‎cardiac echo. ‎Conclusion:‎ A high index of suspicion of KD must be maintained in young infants with ‎prolonged unexplained fever. Accepted criteria should be less restrictive to ‎allow early diagnosis of a typical KD in infants less than 6 months of age. ‎Timely appropriate treatment with IVIG is essential to avoid severe coronary ‎sequels.‎

Keywords: Kawasaki disease, atypical Kawasaki disease, infantile Kawasaki disease, hypo activity‎ ‎

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Authors: A. M. S. S. Amarasiri, A. P. Attanayake, K. A. P. W. Jayatilaka, L. K. B. Mudduwa

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Adriamycin (ADR) is an effective anthracyclin antitumor drug, but its clinical use is limited due to renal toxicity. The leaves of Asparagus falcatus (Family: Liliaceae) have been used in the management of renal diseases since antiquity. In the present investigation, the aqueous leaf extract of A. falcatus was evaluated for acute nephroprotective activity in ADR induced nephrotoxic rats. Nephrotoxicity was induced in healthy male Wistar rats by intraperitoneal administration of ADR 20 mg/kg. The lyophilized powder of the aqueous refluxed (4h) leaf extract of A. falcatus was administered orally at three selected doses; 200, 400 and 600 mg/kg for three consecutive days. Fosinopril sodium (0.09 mg/kg) was used as the standard drug. Administration of the plant extract and the standard drug was commenced 24 hours after the induction of nephrotoxicity to rats. The nephroprotective effect was determined by selected biochemical parameters and by the assessment of histopathology on H and E stained kidney sections. The results were compared to a group of control rats with ADR induced nephrotoxicity. A group of rats administered with the equivalent volume of normal saline served as the healthy control. Administration of ADR 20 mg/kg produced a significant increase in the concentrations of serum creatinine (61%) and urine protein (73%) followed by a significant decrease in serum total protein (21%) and albumin (44%) of the plant extract treated animals compared to the healthy control group (p < 0.05). The aqueous extract of Asparagus falcatus at the three doses; 200, 400 and 600 mg/kg and the standard drug were found to decrease the elevation of concentrations of serum creatinine (33%, 51%, 54% and 42%) and urine protein (8%, 63%, 80% and 86%) respectively. The serum concentrations of total protein (12%, 17%, 29% and 12%) and albumin (3%, 17%, 17% and 16%) were significantly increased compared to the nephrotoxic control group respectively. Assessment of histopathology on H and E stained kidney sections demonstrated that ADR induced renal injury, as evidenced by loss of brush border, cytoplasmic vacuolization, pyknosis in renal tubular epithelial cells, haemorrhages, glomerular congestion and presence of hyaline casts. Treatment with the plant extract and the standard drug resulted in attenuation of the morphological destruction in rats. The results of the present study revealed that the aqueous leaf extract of A. falcatus possesses significant nephroprotective activity against adriamycin induced acute nephrotoxicity. The improved kidney functions were supported with the results of selected biochemical parameters and histological changes observed on H and E stained sections of the kidney tissues in Wistar rats.

Keywords: adriamycin induced nephrotoxicity, asparagus falcatus, biochemical assessment, histopathological assessment, nephroprotective activity

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Authors: Babarina Maria, Andropova Margarita

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Introduction: Hypoparathyroidism (HypoPT) is a rare endocrine disorder with an estimated prevalence of 0.25 per 1000 individuals. The most common cause of HypoPT is the loss of active parathyroid tissue following thyroid or parathyroid surgery. Sometimes permanent postoperative HypoPT occures, manifested by hypocalcemia in combination with low levels of PTH during 6 months or more after surgery. Cognitive impairments in patients with hypocalcemia due to chronic HypoPT are observed, and this can lead to problems and challenges in everyday living: memory loss and impaired concentration, that may be the cause of poor compliance. Clinical case: Patient K., 66 years old, underwent thyroidectomy in 2013 (at the age of 55) because of papillary thyroid cancer T1NxMx, histopathology findings confirmed the diagnosis. 5 years after the surgery, she was followed up on an outpatient basis, TSH levelsonly were monitored, and the dose of levothyroxine was adjusted. In 2018 due to, increasing complaints include tingling and cramps in the arms and legs, memory loss, sleep disorder, fatigue, anxiety, hair loss, muscle pain, tachycardia, positive Chvostek, and Trousseau signs were diagnosed during examination, also in blood analyses: total Ca 1.86 mmol/l (2.15-2.55), Ca++ 0.96 mmol/l (1.12-1.3), P 1.55 mmol/l (0.74-1.52), Mg 0.79 mmol/l (0.66-1.07) - chronic postoperative HypoPT was diagnosed. Therapy was initiated: alfacalcidol 0.5 mcg per day, calcium carbonate 2000 mg per day, cholecalciferol 1000 IU per day, magnesium orotate 3000 mg per day. During the case follow-up, hypocalcemia, hyperphosphatemia persisted, hypercalciuria15.7 mmol/day (2.5-6.5) was diagnosed. Dietary recommendations were given because of the high content of phosphorus rich foods, and therapy was adjusted: the dose of alfacalcidol was increased to 2.5 mcg per day, and the dose of calcium carbonate was reduced to 1500 mg per day. As part of the screening for complications of hypoPT, data for cataracts, Fahr syndrome, nephrocalcinosis, and kidney stone disease were not obtained. However, HypoPT compensation was not achieved, and therefore hydrochlorothiazide 25 mg was initiated, the dose of alfacalcidol was increased to 3 mcg per day, calcium carbonate to 3000 mg per day, magnesium orotate and cholecalciferol were continued at the same doses. Therapeutic goals were achieved: calcium phosphate product <4.4 mmol2/l2, there were no episodes of hypercalcemia, twenty-four-hour urinary calcium excretion was significantly reduced. Conclusion: Timely prescription, careful explanation of drugs usage rules, and monitoring and maintaining blood and urine parameters within the target contribute to the prevention of HypoPT complications development and life-threatening events.

Keywords: hypoparathyroidism, hypocalcemia, hyperphosphatemia, hypercalciuria

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Authors: Shyamani Hettiarachchi, Gopi Kitnasamy

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Background: The potentially high level of physical need and dependency experienced by children with cerebral palsy could affect the quality of life (QOL) of the child, the caregiver and his/her family. Poor QOL in children with cerebral palsy is associated with the parent-child relationship, limited opportunities for social participation, limited access to healthcare services, psychological well-being and the child's physical functioning. Given that children experiencing disabilities have little access to remedial support with an inequitable service across districts in Sri Lanka, and given the impact of culture and societal stigma, there may be differing viewpoints across respondents. Objectives: The aim of this study was to evaluate the psychometric properties of the Tamil version of the Cerebral Palsy Quality of Life for Children (CPQOL-Child) Questionnaire. Design: An instrument development and validation study. Methods: Forward and backward translations of the CPQOL-Child were undertaken by a team comprised of a physiotherapist, speech and language therapist and two linguists for the primary caregiver form and the child self-report form. As part of a pilot phase, the Tamil version of the CPQOL was completed by 45 primary caregivers with children with cerebral palsy and 15 children with cerebral palsy (GMFCS level 3-4). In addition, the primary caregivers commented on the process of filling in the questionnaire. The psychometric properties of test-retest reliability, internal consistency and construct validity were undertaken. Results: The test-retest reliability and internal consistency were high. A significant association (p < 0.001) was found between limited motor skills and poor QOL. The Cronbach's alpha for the whole questionnaire was at 0.95.Similarities and divergences were found between the two groups of respondents. The child respondents identified limited motor skills as associated with physical well-being and autonomy. Akin to this, the primary caregivers associated the severity of motor function with limitations of physical well-being and autonomy. The trend observed was that QOL was not related to the level of impairment but connected to environmental factors by the child respondents. In addition to this, the main concern among primary caregivers about the child's future and on the child's lack of independence was not fully captured by the QOL questionnaire employed. Conclusions: Although the initial results of the CPQOL questionnaire show high test-retest reliability and internal consistency of the instrument, it does not fully reflect the socio-cultural realities and primary concerns of the caregivers. The current findings highlight the need to take child and caregiver perceptions of QOL into account in clinical practice and research. It strongly indicates the need for culture-specific measures of QOL.

Keywords: cerebral palsy, CPQOL, culture, quality of life

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Authors: Sulemana Saibu, Moses Ikpeme

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Background: The severity of the COVID-19 pandemic, brought on by the SARS-CoV-2 coronavirus, has been unprecedented since the 1918 influenza pandemic. SARS-CoV-2 cases of CNS and peripheral nervous system disease, including neurodegenerative disorders and chronic immune-mediated diseases, may be anticipated based on knowledge of past coronaviruses, particularly those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome outbreaks. Although respiratory symptoms are the most common clinical presentation, neurological symptoms are becoming increasingly recognized, raising concerns about their potential role in causing Parkinson's disease, Multiple sclerosis, and Narcolepsy. This systematic review aims to summarize the current evidence by exploring the association between COVID-19 infection and how it may overlap with etiological mechanisms resulting in Narcolepsy, Parkinson's disease, and Multiple sclerosis. Methods: A systematic search was conducted using electronic databases ((PubMed/MedLine, Embase, PsycINFO, ScieLO, Web of Science, ProQuest (Biotechnology, Virology, and AIDS), Scopus, and CINAHL)) to identify studies published between January 2020 and December 2022 that investigated the association between COVID-19 and Parkinson's disease, multiple sclerosis, and Narcolepsy. Per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the review was performed and reported. Study quality was assessed using the Critical Appraisal Skills Programme Checklist and the Joanna Briggs Institute Critical appraisal tools. Results: A total of 21 studies out of 1025 met the inclusion criteria, including 8 studies reporting Parkinson's disease, 11 on multiple sclerosis, and 2 on Narcolepsy. In COVID-19 individuals compared to the general population, Narcolepsy, Parkinson's disease, and multiple sclerosis were shown to have a higher incidence. The findings imply that COVID-19 may worsen the signs or induce multiple sclerosis and Parkinson's disease and may raise the risk of developing Narcolepsy. Further research is required to confirm these connections because the available data is insufficient. Conclusion: According to the existing data, COVID-19 may raise the risk of Narcolepsy and have a causative relationship with Parkinson's disease, multiple sclerosis, and other diseases. More study is required to confirm these correlations and pinpoint probable mechanisms behind these interactions. Clinicians should be aware of how COVID-19 may affect various neurological illnesses and should treat patients who are affected accordingly.

Keywords: COVID-19, parkinson’s disease, multiple sclerosis, narcolepsy, neurological disorders, sars-cov-2, neurodegenerative disorders, chronic immune-mediated diseases

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Authors: Ivonete Teresinha Schulter Buss Heidemann, Michelle Kuntz Durand, Aline Megumi Arakawa-Belaunde, Sandra Mara Corrêa, Leandro Martins Costa Do Araujo, Kamila Soares Maciel

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Primary Health Care is defined as the level of a system of services that enables the achievement of answers to health needs. This level of care produces services and actions of attention to the person in the life cycle and in their health conditions or diseases. Primary Health Care refers to a conception of care model and organization of the health system that in Brazil seeks to reorganize the principles of the Unified Health System. This system is based on the principle of health as a citizen's right and duty of the State. Primary health care has family health as a priority strategy for its organization according to the precepts of the Unified Health System, structured in the logic of new sectoral practices, associating clinical work and health promotion. Thus, this study seeks to know the possibilities and limits of the care developed by professionals working in Primary Health Care. It was conducted by a qualitative approach of the participant action type, based on Paulo Freire's Research Itinerary, which corresponds to three moments: Thematic Investigation; Encoding and Decoding; and, Critical Unveiling. The themes were investigated in a health unit with the development of a culture circle with 20 professionals, from a municipality in southern Brazil, in the first half of 2021. The participants revealed as possibilities the involvement, bonding and strengthening of the interpersonal relationships of the professionals who work in the context of primary care. Promoting welcoming in primary care has favoured care and teamwork, as well as improved access. They also highlighted that care planning, the use of technologies in the process of communication and the orientation of the population enhances the levels of problem-solving capacity and the organization of services. As limits, the lack of professional recognition and the scarce material and human resources were revealed, conditions that generate tensions for health care. The reduction in the number of professionals and the low salary are pointed out as elements that boost the motivation of the health team for the development of the work. The participants revealed that due to COVID-19, the flow of care had as a priority the pandemic situation, which affected health care in primary care, and prevention and health promotion actions were canceled. The study demonstrated that empowerment and professional involvement are fundamental to promoting comprehensive and problem-solving care. However, limits of the teams are observed when exercising their activities, these are related to the lack of human and material resources, and the expansion of public health policies is urgent.

Keywords: health promotion, primary health care, health professionals, welcoming.

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Authors: Tin Yee Ling, Kavita Maravar, Ruzica Ardalic

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Background: Uterine torsion (UT) in pregnancy of more than 45-degree along the longitudinal axis is a rare occurrence, and the aetiology remains unclear. Case: A 34-year-old G2P1 woman with a history of one previous caesarean section presented at 36+2 weeks with sudden onset lower abdominal pain, syncopal episode, and tender abdomen on examination. She was otherwise haemodynamically stable. Cardiotocography showed a pathological trace with initial prolonged bradycardia followed by a subsequent tachycardia with reduced variability. An initial diagnosis of uterine dehiscence was made, given the history and clinical presentation. She underwent an emergency caesarean section which revealed a 180-degree UT along the longitudinal axis, with oedematous left round ligament lying transverse anterior to the uterus and a segment of large bowel inferior to the round ligament. Detorsion of uterus was performed prior to delivery of the foetus, and anterior uterine wall was intact with no signs of rupture. There were no anatomical uterine abnormalities found other than stretched left ovarian and round ligaments, which were repaired. Delivery was otherwise uneventful, and she was discharged on day 2 postpartum. Discussion: UT is rare as the number of reported cases is within the few hundreds worldwide. Generally, the uterus is supported in place by uterine ligaments, which limit the mobility of the structure. The causes of UT are unknown, but risk factors such as uterine abnormalities, increased uterine ligaments’ flexibility in pregnancy, and foetal malposition has been identified. UT causes occlusion of uterine vessels, which can lead to ischaemic injury of the placenta causing premature separation of the placenta, preterm labour, and foetal morbidity and mortality if delivery is delayed. Diagnosing UT clinically is difficult as most women present with symptoms similar to placenta abruption or uterine rupture (abdominal pain, vaginal bleeding, shock), and one-third are asymptomatic. The management of UT involves surgical detorsion of the uterus and delivery of foetus via caesarean section. Extra vigilance should be taken to identify the anatomy of the uterus experiencing torsion prior to hysterotomy. There have been a few cases reported with hysterotomy on posterior uterine wall for delivery of foetus as it may be difficult to identify and reverse a gravid UT when foetal well-being is at stake. Conclusion: UT should be considered a differential diagnosis of acute abdominal pain in pregnancy. It is crucial that the torsion is addressed immediately as it is associated with maternal and foetal morbidity and mortality.

Keywords: uterine torsion, pregnancy complication, abdominal pain, torted uterus

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Authors: Suteera Pradubwong, Pattama Surit, Sumalee Pongpagatip, Tharinee Pethchara, Bowornsilp Chowchuen

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Background: Cleft lip and palate (CLP) is a congenital anomaly of the lip and palate that is caused by several factors. It was found in approximately one per 500 to 550 live births depending on nationality and socioeconomic status. The Tawanchai Center and out-patients surgical room of Srinagarind Hospital are responsible for providing care to patients with CLP (starting from birth to adolescent) and their caregivers. From the observations and interviews with nurses working in these units, they reported that both patients and their caregivers confronted many problems which affected their physical and mental health. Based on the Soukup’s model (2000), the researchers used evidence triggers from clinical practice (practice triggers) and related literature (knowledge triggers) to investigate the problems. Objective: The purpose of this study was to investigate the problems of care for patients with CLP in the Tawanchai Center and out-patient surgical room of Srinagarind Hospital. Material and Method: The descriptive method was used in this study. For practice triggers, the researchers obtained the data from medical records of ten patients with CLP and from interviewing two patients with CLP, eight caregivers, two nurses, and two assistant workers. Instruments for the interview consisted of a demographic data form and a semi-structured questionnaire. For knowledge triggers, the researchers used a literature search. The data from both practice and knowledge triggers were collected between February and May 2016. The quantitative data were analyzed through frequency and percentage distributions, and the qualitative data were analyzed through a content analysis. Results: The problems of care gained from practice and knowledge triggers were consistent and were identified as holistic issues, including 1) insufficient feeding, 2) risks of respiratory tract infections and physical disorders, 3) psychological problems, such as anxiety, stress, and distress, 4) socioeconomic problems, such as stigmatization, isolation, and loss of income, 5)spiritual problems, such as low self-esteem and low quality of life, 6) school absence and learning limitation, 7) lack of knowledge about CLP and its treatments, 8) misunderstanding towards roles among the multidisciplinary team, 9) no available services, and 10) shortage of healthcare professionals, especially speech-language pathologists (SLPs). Conclusion: From evidence-triggers, the problems of care affect the patients and their caregivers holistically. Integrated long-term care by the multidisciplinary team is needed for children with CLP starting from birth to adolescent. Nurses should provide effective care to these patients and their caregivers by using a holistic approach and working collaboratively with other healthcare providers in the multidisciplinary team.

Keywords: evidence-triggers, cleft lip, cleft palate, problems of care

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Authors: Neha Batra Bali, Monika Tomar, Vinay Gupta

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A reagentless biosensor for detection of urea based on ZnO-CuO composite thin film is presented in following work. Biosensors have immense potential for varied applications ranging from environmental to clinical testing, health care, and cell analysis. Immense growth in the field of biosensors is due to the huge requirement in today’s world to develop techniques which are both cost effective and accurate for prevention of disease manifestation. The human body comprises of numerous biomolecules which in their optimum levels are essential for functioning. However mismanaged levels of these biomolecules result in major health issues. Urea is one of the key biomolecules of interest. Its estimation is of paramount significance not only for healthcare sector but also from environmental perspectives. If level of urea in human blood/serum is abnormal, i.e., above or below physiological range (15-40mg/dl)), it may lead to diseases like renal failure, hepatic failure, nephritic syndrome, cachexia, urinary tract obstruction, dehydration, shock, burns and gastrointestinal, etc. Various metal nanoparticles, conducting polymer, metal oxide thin films, etc. have been exploited to act as matrix to immobilize urease to fabricate urea biosensor. Amongst them, Zinc Oxide (ZnO), a semiconductor metal oxide with a wide band gap is of immense interest as an efficient matrix in biosensors by virtue of its natural abundance, biocompatibility, good electron communication feature and high isoelectric point (9.5). In spite of being such an attractive candidate, ZnO does not possess a redox couple of its own which necessitates the use of electroactive mediators for electron transfer between the enzyme and the electrode, thereby causing hindrance in realization of integrated and implantable biosensor. In the present work, an effort has been made to fabricate a matrix based on ZnO-CuO composite prepared by pulsed laser deposition (PLD) technique in order to incorporate redox properties in ZnO matrix and to utilize the same for reagentless biosensing applications. The prepared bioelectrode Urs/(ZnO-CuO)/ITO/glass exhibits high sensitivity (70µAmM⁻¹cm⁻²) for detection of urea (5-200 mg/dl) with high stability (shelf life ˃ 10 weeks) and good selectivity (interference ˂ 4%). The enhanced sensing response obtained for composite matrix is attributed to the efficient electron exchange between ZnO-CuO matrix and immobilized enzymes, and subsequently fast transfer of generated electrons to the electrode via matrix. The response is encouraging for fabricating reagentless urea biosensor based on ZnO-CuO matrix.

Keywords: biosensor, reagentless, urea, ZnO-CuO composite

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Authors: Aneal Khan, Elleine Allapitan, Desmond Koo, Katherine-Ann Piedalue, Shaneel Pathak, Utkarsh Subnis

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Background: Disease management of metabolic, genetic disorders is long-term and can be cumbersome to patients and caregivers. Patient-Reported Outcome Measures (PROMs) have been a useful tool in capturing patient perspectives to help enhance treatment compliance and engagement with health care providers, reduce utilization of emergency services, and increase satisfaction with their treatment choices. Currently, however, PROMs are collected during infrequent and decontextualized clinic visits, which makes translation of patient experiences challenging over time. The GRIT study aims to evaluate a digital health journal application called Zamplo that provides a personalized health diary to record self-reported health outcomes accurately and efficiently in patients with metabolic, genetic disorders. Methods: This is a randomized controlled trial (RCT) (1:1) that assesses the efficacy of Zamplo to increase patient activation (primary outcome), improve healthcare satisfaction and confidence to manage medications (secondary outcomes), and reduce costs to the healthcare system (exploratory). Using standardized online surveys, assessments will be collected at baseline, 1 month, 3 months, 6 months, and 12 months. Outcomes will be compared between patients who were given access to the application versus those with no access. Results: Seventy-seven patients were recruited as of November 30, 2021. Recruitment for the study commenced in November 2020 with a target of n=150 patients. The accrual rate was 50% from those eligible and invited for the study, with the majority of patients having Fabry disease (n=48) and the remaining having Pompe disease and mitochondrial disease. Real-time clinical responses, such as pain, are being measured and correlated to disease-modifying therapies, supportive treatments like pain medications, and lifestyle interventions. Engagement with the application, along with compliance metrics of surveys and journal entries, are being analyzed. An interim analysis of the engagement data along with preliminary findings from this pilot RCT, and qualitative patient feedback will be presented. Conclusions: The digital self-care journal provides a unique approach to disease management, allowing patients direct access to their progress and actively participating in their care. Findings from the study can help serve the virtual care needs of patients with metabolic, genetic disorders in North America and the world over.

Keywords: eHealth, mobile health, rare disease, patient outcomes, quality of life (QoL), pain, Fabry disease, Pompe disease

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Authors: Lakmali Anthony, Madeline Gillies

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Background: Colorectal cancer (CRC) is usually managed with surgical resection. Many of the outcomes traditionally used to define successful operative management, such as resection margin, do not adequately reflect patients’ experience. Patient-reported outcomes (PRO), such as Health-Related Quality of life (HRQoL), provide a means by which the impact of surgery for cancer can be reported in a patient-centered way. HRQoL has previously been shown to be impacted by psychosocial, behavioral and disease-specific characteristics. This exploratory cross-sectional study aims to; (1) describe postoperative HRQoL in patients who underwent primary resection in a regional Australian hospital; (2) describe the prevalence of anxiety, depression and clinically significant fear of cancer recurrence (FCR) in this population; and (3) identify demographic, psychosocial, disease and treatment factors associated with poorer self-reported HRQoL. Methods: Consecutive patients who had resection of colorectal cancer in a single regional Australian hospital between 2015 and 2022 were eligible. Participants were asked to complete a survey instrument designed to assess HRQoL, as well as validated instruments that assess several other psychosocial PROs hypothesized to be associated with HRQoL; emotional distress, fear of cancer recurrence, social support, dispositional optimism, body image and spirituality. Demographic and disease-specific data were also collected via medical record review. Results: Forty-six patients completed the survey. Clinically significant levels of fear of recurrence as well as emotional distress, were present in this group. Many domains of HRQoL were significantly worse than an Australian reference population for CRC. Demographic and disease factors associated with poor HRQoL included smoking and ongoing adjuvant systemic therapy. The primary operation was not associated with HRQoL; however, the operative approach (laparoscopic vs. open) was associated with HRQoL for these patients. All psychosocial factors measured were associated with HRQoL, including cancer worry, emotional distress, body image and dispositional optimism. Conclusion: HRQoL is an important outcome in surgery for both research and clinical practice. This study provides an overview of the quality of life in a regional Australian population of postoperative colorectal cancer patients and the factors that affect it. Understanding HRQoL and awareness of patients particularly vulnerable to poor outcomes should be used to aid the informed consent and shared decision-making process between surgeon and patient.

Keywords: surgery, colorectal, cancer, PRO, HRQoL

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Authors: Heena Dabas, Anju Paul, Suman Chaurasia, Ramesh Agarwal, M. Jeeva Sankar, Anurag Bajpai, Manju Saksena

Abstract:

Background: Traumatic lumbar puncture (LP) is a common occurrence and causes substantial diagnostic ambiguity. There is paucity of data regarding its epidemiology. Objective: To assess the incidence and risk factors of traumatic LP in newborns. Design/Methods: In a prospective cohort study, all inborn neonates admitted in NICU and planned to undergo LP for a clinical indication of sepsis were included. Neonates with diagnosed intraventricular hemorrhage (IVH) of grade III and IV were excluded. The LP was done by operator - often a fellow or resident assisted by bedside nurse. The unit has policy of not routinely using any sedation/analgesia during the procedure. LP is done by 26 G and 0.5-inch-long hypodermic needle inserted in third or fourth lumbar space while the infant is in lateral position. The infants were monitored clinically and by continuous measurement of vital parameters using multipara monitor during the procedure. The occurrence of traumatic tap along with CSF parameters and other operator and assistant characteristics were recorded at the time of procedure. Traumatic tap was defined as presence of visible blood or more than 500 red blood cells on microscopic examination. Microscopic trauma was defined when CSF is not having visible blood but numerous RBCs. The institutional ethics committee approved the study protocol. A written informed consent from the parents and the health care providers involved was obtained. Neonates were followed up till discharge/death and final diagnosis was assigned along with treating team. Results: A total of 362 (21%) neonates out of 1726 born at the hospital were admitted during the study period (July 2016 to January, 2017). Among these neonates, 97 (26.7%) were suspected of sepsis. A total of 54 neonates were enrolled who met the eligibility criteria and parents consented to participate in the study. The mean (SD) birthweight was 1536 (732) grams and gestational age 32.0 (4.0) weeks. All LPs were indicated for late onset sepsis at the median (IQR) age of 12 (5-39) days. The traumatic LP occurred in 19 neonates (35.1%; 95% C.I 22.6% to 49.3%). Frank blood was observed in 7 (36.8%) and in the remaining, 12(63.1%) CSF was detected to have microscopic trauma. The preliminary risk factor analysis including birth weight, gestational age and operator/assistant and other characteristics did not demonstrate clinically relevant predictors. Conclusion: A significant number of neonates requiring lumbar puncture in our study had high incidence of traumatic tap. We were not able to identify modifiable risk factors. There is a need to understand the reasons and further reduce this issue for improving management in NICUs.

Keywords: incidence, newborn, traumatic, lumbar puncture

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Authors: Meryam Labyad, Karima Fakiri, Widad Lahmini, Ghizlane Draiss, Mohamed Bouskraoui, Nadia Ouzennou

Abstract:

Background: Asthma is the most common chronic disease in children, affecting nearly 235 million people worldwide (OMS). In Morocco, asthma is much more common in children than in adults; the prevalence rate in children between 13 and 14 years of age is 20%.1 This pathology is marked by high morbidity, a significant impact on the quality of life and development of children 2 This requires a rigorous management strategy in order to achieve clinical control and reduce any risk to the patient 3 A search for aggravating factors is mandatory if a child has difficulty maintaining good asthma control. The objective of the present study is to describe asthma control during this confinement period in children aged 4 to 11 years followed by a pneumo-paediatric consultation. For children whose asthma is not controlled, a search for associations with promoting factors and adherence to treatment is also among the objectives of the study. Knowing the level of asthma control and influencing factors is a therapeutic priority in order to reduce hospitalizations and emergency care use. Objective: To assess asthma control and determine the factors influencing asthma levels in children with asthma during confinement following the COVID 19 pandemic. Method: Prospective cross-sectional study by questionnaire and structured interview among 66 asthmatic children followed in pediatric pneumology consultation at the CHU MED VI of Marrakech from 13/06/2020 to 13/07/2020, asthma control was assessed by the Childhood Asthma Control Test (C-ACT). Results: 66 children and their parents were included (mean age is 7.5 years), asthma was associated with allergic rhinitis (13.5% of cases), conjunctivitis (9% of cases), eczema (12% of cases), occurrence of infection (10.5% of cases). The period of confinement was marked by a decrease in the number of asthma attacks translated by a decrease in the number of emergency room visits (7.5%) of these asthmatic children, control was well controlled in 71% of the children, this control was significantly associated with good adherence to treatment (p<0.001), no infection (p<0.001) and no conjunctivitis (p=002) or rhinitis (p<0.001). This improvement in asthma control during confinement can be explained by the measures taken in the Kingdom to prevent the spread of COVID 19 (school closures, reduction in industrial activity, fewer means of transport, etc.), leading to a decrease in children's exposure to triggers, which justifies the decrease in the number of children having had an infection, allergic rhinitis or conjunctivitis during this period. In addition, the close monitoring of parents resulted in better therapeutic adherence (42.4% were fully observant). Confinement was positively perceived by 68% of the parents; this perception is significantly associated with the level of asthma control (p<0.001). Conclusion: Maintaining good control can be achieved through improved therapeutic adherence and avoidance of triggers, both of which were achieved during the containment period following the VIDOC pandemic 19.

Keywords: Asthma, control , COVID-19 , children

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Authors: Martyna Chotomska, Aleksandra Studzinska, Marta Lisowska, Justyna Szubert, Aleksandra Tabis, Jacek Bania, Arkadiusz Miazek

Abstract:

Objectives: Assessing antigen-specific T cell responses is of utmost importance for the pre-clinical testing of prototype vaccines against intracellular pathogens and tumor antigens. Mainly two types of in vitro assays are used for this purpose 1) enzyme-linked immunospot (ELISpot) and 2) intracellular cytokine staining (ICS). Both are time-consuming, relatively expensive, and require manual dexterity. Here, we assess if a straightforward detection of luciferase activity in blood samples of transgenic reporter mice expressing a secreted Lucia luciferase under the transcriptional control of IFN-γ promoter parallels the sensitivity of IFNγ ELISpot assay. Methods: IFN-γ-LUCIA mouse strain carrying multiple copies of Lucia luciferase transgene under the transcriptional control of IFNγ minimal promoter were generated by pronuclear injection of linear DNA. The specificity of transgene expression and mobilization was assessed in vitro using transgenic splenocytes exposed to various mitogens. The IFN-γ-LUCIA mice were immunized with 50mg of ovalbumin (OVA) emulsified in incomplete Freund’s adjuvant three times every two weeks by subcutaneous injections. Blood samples were collected before and five days after each immunization. Luciferase activity was assessed in blood serum. Peripheral blood mononuclear cells were separated and assessed for frequencies of OVA-specific IFNγ-secreting T cells. Results: We show that in vitro cultured splenocytes of IFN-γ-LUCIA mice respond by 2 and 3 fold increase in secreted luciferase activity to T cell mitogens concanavalin A and phorbol myristate acetate, respectively but fail to respond to B cell-stimulating E.coli lipopolysaccharide. Immunization of IFN-γ-LUCIA mice with OVA leads to over 4 fold increase in luciferase activity in blood serum five days post-immunization with a barely detectable increase in OVA-specific, IFNγ-secreting T cells by ELISpot. Second and third immunizations, further increase the luciferase activity and coincidently also increase the frequencies of OVA-specific T cells by ELISpot. Conclusions: We conclude that minimally invasive monitoring of luciferase secretions in blood serum of IFN-γ-LUCIA mice constitutes a sensitive method for evaluating primary and memory Th1 responses to protein antigens. As such, this method may complement existing methods for rapid immunogenicity assessment of prototype vaccines.

Keywords: ELISpot, immunogenicity, interferon-gamma, reporter mice, vaccines

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Authors: Ofelia Loani Elvir Lazo, Roya Yumul, David Chernobylsky, Omar Durra

Abstract:

Background: It is crucial to detect the patient’s existing anxiety to assist patients in a perioperative setting which is to be caused by the fear associated with surgical and anesthetic complications. However, the current gold standard for assessing patient anxiety, the STAI, is problematic to use in the preoperative setting, given the duration and concentration required to complete the 40-item questionnaire. Our primary aim in the study is to investigate the correlation of the Yumul Visual Facial Anxiety Scale (VFAS) and Numerical Verbal Rating Scale (NVRS) to State-Trait Anxiety Inventory (STAI) to determine the optimal anxiety scale to use in the perioperative setting. Methods: A clinical study of patients undergoing various surgeries was conducted utilizing each of the preoperative anxiety scales. Inclusion criteria included patients undergoing elective surgeries, while exclusion criteria included patients with anesthesia contraindications, inability to comprehend instructions, impaired judgement, substance abuse history, and those pregnant or lactating. 293 patients were analyzed in terms of demographics, anxiety scale survey results, and anesthesia data via Spearman Coefficients, Chi-Squared Analysis, and Fischer’s exact test utilized for comparative analysis. Results: Statistical analysis showed that VFAS had a higher correlation to STAI than NVRS (rs=0.66, p<0.0001 vs. rs=0.64, p<0.0001). The combined VFAS-Categorization Scores showed the highest correlation with the gold standard (rs=0.72, p<0.0001). Subgroup analysis showed similar results. STAI evaluation time (247.7 ± 54.81 sec) far exceeds VFAS (7.29 ± 1.61 sec), NVRS (7.23 ± 1.60 sec), and Categorization scales (7.29 ± 1.99 sec). Patients preferred VFAS (54.4%), Categorization (11.6%), and NVRS (8.8%). Anesthesiologists preferred VFAS (63.9%), NVRS (22.1%), and Categorization Scales (14.0%). Of note, the top five causes of preoperative anxiety were determined to be waiting (56.5%), pain (42.5%), family concerns (40.5%), no information about surgery (40.1%), or anesthesia (31.6%). Conclusıons: Both VFAS and Categorization tests also take significantly less time than STAI, which is critical in the preoperative setting. Combined VFAS-Categorization Score (VCS) demonstrates the highest correlation to the gold standard, STAI. Among both patients and anesthesiologists, VFAS was the most preferred scale. This forms the basis of the Yumul Faces Anxiety Scale, designed for quick quantization and assessment in the preoperative setting while maintaining a high correlation to the golden standard. Additional studies using the formulated Yumul Faces Anxiety Scale are merited.

Keywords: numerical verbal anxiety scale, preoperative anxiety, state-trait anxiety inventory, visual facial anxiety scale

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Authors: Muhammad Qamar Masood, Syed Abbas Raza, Umar Yousaf Raja, Imran Hassan, Bilal Afzal, Muhammad Aleem Zahir, Atika Shaheer

Abstract:

Background: Cardiovascular disease (CVD) is a major burden among people with type 2 diabetes (T2D) with 1 in 3 reported to have CVD. Therefore, understanding real-world clinical characteristics and prescribing patterns could help in better care. Objective: The CONVERGE (Cardiovascular Outcomes and Value in the Real world with GLP-1RAs) study characterized demographics and medication usage patterns in T2D intensified (add-on to metformin) overall population. The data were further divided into subgroups {dipeptidyl peptidase-4 inhibitors (DPP-4is), sulfonylureas (SUs), insulins, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is)}, according to the latest prescribed antidiabetic agent (ADA) in India/Pakistan/Thailand. Here, we report findings from Pakistan. Methods: A multi-center retrospective study utilized data from medical records between 13-Sep-2008 (post-market approval of GLP-1RAs) and 31-Dec-2017 in adults (≥18-year-old). The data for this study were collected from 05 centers / institutes located in major cities of Pakistan, including Karachi, Lahore, Islamabad, and Multan. These centers included National Hospital, Aga Khan University Hospital, Diabetes Endocrine Clinic Lahore, Shifa International Hospital, Mukhtar A Sheikh Hospital Multan. Data were collected at start of medical record and at 6 or 12-months prior to baseline based on variable type; analyzed descriptively. Results: Overall, 1,010 patients were eligible. At baseline, overall mean age (SD) was 51.6 (11.3) years, T2D duration was 2.4 (2.6) years, HbA1c was 8.3% (1.9) and 35% received ≥1CVD medications in the past 1-year (before baseline). Most frequently prescribed ADAs post-metformin were DPP-4is and SUs (~63%). Only 6.5% received GLP-1RAs and SGLT-2is were not available in Pakistan during the study period. Overall, it took a mean of 4.4 years and 5 years to initiate GLP-1RAs and SGLT-2is, respectively. In comparison to other subgroups, more patients from GLP-1RAs received ≥3 types of ADA (58%), ≥1 CVD medication (64%) and had higher body mass index (37kg/m2). Conclusions: Utilization of GLP-1RAs and SGLT-2is was low, took longer time to initiate and not before trying multiple ADAs. This may be due to lack of evidence for CV benefits for these agents during the study period. The planned phase 2 of the CONVERGE study can provide more insights into utilization and barriers to prescribe GLP-1RAs and SGLT-2is post 2018 in Pakistan.

Keywords: type 2 diabetes, GLP-1RA, treatment intensification, cardiovascular disease

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