Beyond Amyloid: A Machine Learning-Driven Approach Reveals Properties of Potent GSK-3ß Inhibitors Targeting Neurofibrillary Tangles.

Current treatments for Alzheimer's disease (AD) focus on slowing memory and cognitive decline, but none offer curative outcomes. This study aims to explore and curate the common properties of active, drug-like molecules that modulate glycogen synthase kinase 3ß (GSK-3ß), a well-documented kinase with increased activity in tau hyperphosphorylation and neurofibrillary tangles-hallmarks of AD pathology. Leveraging quantitative structure-activity relationship (QSAR) data from the PubChem and ChEMBL databases, we employed seven machine learning models: logistic regression (LogR), k-nearest neighbors (KNN), random forest (RF), support vector machine (SVM), extreme gradient boosting (XGB), neural networks (NNs), and ensemble majority voting. Our goal was to correctly predict active and inactive compounds that inhibit GSK-3ß activity and identify their key properties. Among the six individual models, the NN demonstrated the highest performance with a 79% AUC-ROC on unbalanced external validation data, while the SVM model was superior in accurately classifying the compounds. The SVM and RF models surpassed NN in terms of Kappa values, and the ensemble majority voting model demonstrated slightly better accuracy to the NN on the external validation data. Feature importance analysis revealed that hydrogen bonds, phenol groups, and specific electronic characteristics are important features of molecular descriptors that positively correlate with active GSK-3ß inhibition. Conversely, structural features like imidazole rings, sulfides, and methoxy groups showed a negative correlation. Our study highlights the significance of structural, electronic, and physicochemical descriptors in screening active candidates against GSK-3ß. These predictive features could prove useful in therapeutic strategies to understand the important properties of GSK-3ß candidate inhibitors that may potentially benefit non-amyloid-based AD treatments targeting neurofibrillary tangles.

Conceptual framework for establishing the African Stroke Organization.

Africa is the world's most genetically diverse, second largest, and second most populous continent, with over one billion people distributed across 54 countries. With a 23% lifetime risk of stroke, Africa has some of the highest rates of stroke worldwide and many occur in the prime of life with huge economic losses and grave implications for the individual, family, and the society in terms of mental capital, productivity, and socioeconomic progress. Tackling the escalating burden of stroke in Africa requires prioritized, multipronged, and inter-sectoral strategies tailored to the unique African epidemiological, cultural, socioeconomic, and lifestyle landscape. The African Stroke Organization (ASO) is a new pan-African coalition that brings together stroke researchers, clinicians, and other health-care professionals with participation of national and regional stroke societies and stroke support organizations. With a vision to reduce the rapidly increasing burden of stroke in Africa, the ASO has a four-pronged focus on (1) research, (2) capacity building, (3) development of stroke services, and (4) collaboration with all stakeholders. This will be delivered through advocacy, awareness, and empowerment initiatives to bring about people-focused changes in policy, clinical practice, and public education. In the spirit of the African philosophy of Ubuntu "I am because we are," the ASO will harness the power of diversity, inclusiveness, togetherness, and team work to build a strong, enduring, and impactful platform for tackling stroke in Africa.

Chronic HIV infection and health related quality of life in resource poor settings-an assessment from South East Nigeria.

BACKGROUND: Health-related quality of life reflects a patient's general subjective perception of the effect of an illness or intervention on physical, psychological and social aspects of daily life. HIV infection is a major public health problem especially in developing countries where poor health infrastructure and poverty are prevalent. This paper addresses the quality of life in patients with chronic HIV infection in South East Nigeria and addresses issues that may help improve the current situation. METHODS: A cross-sectional survey was carried out at the University of Nigeria Teaching Hospital, Enugu, to assess patients with HIV receiving antiretroviral therapy (ART) using a validated structured questionnaire (WHOQoL-BREF). Ethical clearance for the study was obtained. Study period was from October - December, 2017. Data obtained was analysed. RESULTS: A total of 389 HIV patients consented to the study. Over 70% were aged 18- 45 years and majority were females. Females had a higher quality of life score with respect to the domain of psychological health while males had a higher score with respect to the environmental domain. Older age and presence of co-morbidities were significantly associated with affectation of physical health while younger age was associated with affectation of psychological health domain. CONCLUSION: HIV impairs the quality of life for affected individuals in South East Nigeria especially across the domains of physical and psychological health. No age group is spared. The presence of co-morbidities significantly reduces quality of life in these patients. Younger patients may require mental health services in the management of their disease.

Levetiracetam-induced rage and suicidality: Two case reports and review of literature.

BACKGROUND: Levetiracetam-induced rage is a rare neurobehavioral adverse effect of levetiracetam that is characterized by seething rage, uncontrollable anger, fits of fury, depression, violence, and suicidal tendencies. It occurs more in patients with prior mood or psychotic disturbances. No such case has been reported in Nigeria. METHOD: We report two cases of levetiracetam-induced rage. The first patient was a 29-year-old male with a 14-year history of intractable posttraumatic epilepsy. He was initially placed on sodium valproate and phenobarbitone and later had phenobarbitone replaced with levetiracetam. Within the first week of initiating levetiracetam, he became aggressive, bursted into fits of fury, and attacked his siblings. Levetiracetam was stopped, and the seething rage ceased only to reappear when it was reintroduced; hence, the complete withdrawal of levetiracetam. Naranjo probability score for adverse drug reaction was 8. RESULTS: The second patient was a 23-year-old lady who developed seething rage and made several attempts to kill herself with a knife following addition of levetiracetam to the clonazepam and carbamazepine that she was taking for treatment-resistant epilepsy. Withdrawal and reintroduction of levetiracetam by the relatives led to cessation and reemergence, respectively, of the rage and suicidal tendencies. Naranjo score was 8. Levetiracetam was discontinued. CONCLUSION: Neuropsychiatric evaluation for prior mood or psychiatric disorders in those initiating levetiracetam therapy is suggested alongside monitoring for early features of levetiracetam-induced rage by both caregivers and physicians. This will help stem the morbidity and potential mortality associated with this life-threatening adverse drug reaction.

Headache prevalence and its characterization amongst hospital workers in Enugu, South East Nigeria.

BACKGROUND: Headaches are probably the commonest neurological complaint worldwide. Amongst workers it contributes significantly to loss of productive time and work efficiency. It is an important cause of disability and reduced quality of life. The prevalence and pattern amongst health workers in Africa has not been extensively studied. OBJECTIVE: This epidemiological sampling-based preliminary study examined the frequency and pattern of headache in a population of health workers of a tertiary hospital in Enugu, South East Nigeria. METHODS: Study participants, recruited by balloting, completed a self-administered questionnaire to screen for headache and its associations (defined as headache unrelated to fever and experienced within 6 months prior to the date the questionnaire was administered). Data analysis was by SPSS version 16. Ethical approval was obtained from the Hospital Ethical Review Committee. RESULTS: One hundred and thirty-three workers aged 18 - 70 years, were evaluated (males 53.4%, n=71 and females 46.6%, n=62). Headache was experienced by 88% of workers with primary headaches constituting more than 70% of cases. Females were more affected in both instances. Primary and secondary headaches occurred more in younger and older workers respectively and the association was significant (P <0.05). Headaches were not a significant cause of disability and loss of productivity. CONCLUSION: Headaches are very prevalent in hospital workers in Enugu, Nigeria. In older workers screening for underlying causes is indicated. Disability, work absenteeism and loss of productive time are minimal despite the high headache prevalence.

Knowledge, attitude and practice of epilepsy among community residents in Enugu, South East Nigeria.

PURPOSE: The understanding of the opinions of the Nigerian public about epilepsy and its treatment is relevant to the reduction of the large treatment gap that exists in management of the condition. The major aim of this study was to determine the knowledge and attitudes of urban dwellers to epilepsy and its treatment and to identify the gaps in knowledge that could pose as barriers in the treatment and care of epilepsy patients within the community. METHOD: This cross-sectional and descriptive study was carried out in one of the districts of Enugu metropolis, Nigeria. Data collection was by means of a semi-structured validated questionnaire. RESULTS: The mean score in knowledge was low, 48.1±18.8%; higher in females (50.6±18.6%, p=0.03 and those who had witnessed seizures in the past 49.7±18.8, p<0.01. On attitudes, 61.8% of the respondents accepted that it is right if sufferers married but most (93.2%) would not marry them and 87.2% would not allow them to have children or make a new acquaintance by working or playing with them (72.8%). There were no significant differences in the attitude scores of respondents with different levels of education. CONCLUSION: The level of knowledge of epilepsy in among urban dwellers in SE Nigeria is low and fraught with misconceptions and gaps. There were no significant differences in the attitude scores of respondents with different levels of education. There is a need for a multi-faceted educational interventions directed at improving the awareness and understanding of the condition by all segments of the society.

Ischaemic stroke in hyperthyroidism without cardiac arrhythmia. A case report from south east Nigeria.

BACKGROUND: The relationship between hyperthyroidism and stroke is well established in the setting of atrial fibrillation. However there is limited literature for ischaemic stroke occuring in hyperthyroidism without cardiac arrhythmia. No such case had been described in South East Nigeria. METHOD: This report highlights a case of ischaemic lacunar infarction in an elderly Nigerian woman with reemergent thyrotoxicosis, without atrial fibrillation. RESULT: A 75- year old retired female teacher presented with a painless goiter of 3 years duration and right sided hemiplegia of 2 months duration. She had sub-total thyroidectomy 32 years ago for thyrotoxicosis with subsequent good outcome and had been managed for diabetes mellitus for 13 years with good glycaemic control. She was not a known hypertensive. She was thyrotoxic on examination with a large non-tender goiter. There was sinus tachycardia. She had a right sided facial nerve palsy and ipsilateral spastic hemiplegia. Sensations were spared. Results of investigations confirmed hyperthyroidism while brain CT scan was unremarkable except for cerebral atrophy. She had no other associated risk factor associated with hyperthyroidism. Within two weeks of admission she was stabilized on anti-thyroid and anti-diabetic medications, her motor functions significantly recovered and she was independent. She was discharged to be followed up at the out-patients' clinic. CONCLUSION: Ischaemic stroke may present in hyperthyroid patients without atrial fibrillation. This possibility needs to be entertained despite the absence of cardiac arrhythmia or other well established factors for cardioembolic stroke. There is a need for more studies on this relationship.

Critical care of myasthenia gravis in a resource poor setting: a study of South East Nigeria.

BACKGROUND: Myasthenia gravis presenting as a neurologic emergency warrants management in a critical care unit. In resource poor settings which typify much of Africa, this can be very challenging even in tertiary centers with consequently unfavorable outcomes. AIM: This study evaluated the outcomes of intensive care management of patients with myasthenia gravis in a regional teaching hospital in South East Nigeria. METHODS: A retrospective study was undertaken of patients admitted into the intensive care unit of the University of Nigeria Teaching Hospital Enugu, South East Nigeria, with myasthenia gravis as a neurologic emergency. This study covered a 13-year period from 1992 to 2004. From the case records demographic data, clinical features and details of clinical management, complications, and outcomes were determined and subjected to analysis. RESULTS: The median age at presentation was 29 years (range, 20 to 42 y) with male:female ratio of 1:2.7. The median duration of illness before presentation to the intensive care unit was 7 months (range, 1 wk to 3 y). The median duration of stay in the unit was 15 days (range, 1 to 36 d). Two cases of septicemia and acute renal failure were recorded. The overall mortality rate was 27.3%. CONCLUSION: Sepsis is a major factor contributing to poor outcomes among patients with myasthenia gravis managed in critical care units in Nigeria. Vigorous and concerted efforts should be made to make intensive care units more effective in Africa.