Severe Neurocognitive Impairment Research Articles

Correlations between SHBG, Sex Hormones, Inflammation, and Neurocognitive Decline in Alzheimer's Disease:A Retrospective Study.

Alzheimer's Disease (AD) is characterized by a progressive neurodegenerative process leading to cognitive decline and functional impairment. Endocrine factors, particularly sex hormones and their binding proteins, play a critical role in AD pathophysiology. Understanding the relationship between these factors and AD is essential for developing targeted interventions. To investigate the potential links between sex hormone binding globulin (SHBG) levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in patients with AD. A retrospective case-control investigation was conducted with 110 AD patients who were admitted to our hospital from January 2021 to December 2023, and the patients were classified into either a mild neurocognitive impairment group (n=59) or a moderate to severe neurocognitive impairment group (n=51) according to their cognitive function. Correlation and regression analyses were conducted to examine relationships between variable factors. The study revealed a significant neurocognitive decline in AD patients with lower Mini-- Mental State Examination (MMSE) and higher AD Assessment Scale-Cognitive Subscale (ADAS- Cog) scores in the moderate to severe neurocognitive impairment group compared to the mild neurocognitive impairment group. Additionally, the moderate to severe neurocognitive impairment group significantly increased for SHBG, estradiol, progesterone inflammatory markers [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β)). It decreased for follicle-stimulating hormone (FSH) and luteinizing hormone (LH)]. Moreover, significant positive correlations were found between SHBG levels and ADAS-Cog scores, and significant negative correlations were found between SHBG levels and MMSE scores. FSH showed significant negative correlations with the MMSE score, while certain inflammatory markers demonstrated significant correlations with neurocognitive abilities. The correlation between sex hormones and inflammatory factors is weak. FSH, LH, SHBG, CRP, IL-6, TNF-α, and IL-1β are risk factors for neurocognitive impairment, while E2 and P are protective factors. The study provides evidence of significant correlations between SHBG levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in AD patients.

Risk factors of obstructive sleep apnea syndrome in the developmental age

Background: Obstructive Sleep Apnea Syndrome (OSAS) is a prevalent respiratory sleep disorder in children, associated with severe health consequences, including hypertension, cardiac dysfunction, and neurocognitive impairment. Despite extensive research on OSAS in adults, the risk factors for pediatric OSAS remain underexplored. Objective: This literature review aims to identify and present the key risk factors associated with pediatric OSAS based on contemporary studies. Methods: A systematic search of the PubMed and Scopus databases was conducted for literature published between 2016 and 2024. Search terms included “obstructive sleep apnea,” “children,” and “risk factors.” A total of 93 relevant studies were reviewed after excluding non-pediatric and irrelevant papers from an initial pool of 283. Results: The most commonly identified risk factors for pediatric OSAS include adenoid and tonsillar hypertrophy, obesity, craniofacial abnormalities, and asthma. Additional risk factors such as allergic rhinitis, recurrent upper respiratory infections, nasal stenosis, congenital diseases, low vitamin D levels, and preterm birth were also noted. Conclusion: Pediatric OSAS is influenced by multiple factors, including anatomical, physiological, and genetic components. Further research is required to explore emerging risk factors, such as role of vitamin D deficiency and microbiota, and to clarify the impact of variables like ethnicity and breastfeeding.

Brain Imaging in New-Onset Seizure of Children Living With Human Immunodeficiency Virus in Zambia

BackgroundThere are an estimated 1.5 million children living with human immunodeficiency virus (CLHIV), most residing in sub-Saharan Africa. A common hospital presentation of CLHIV is new-onset seizure, for which imaging is helpful but not routinely performed due to scarce resources. We present imaging findings and their association with clinical risk factors and outcomes in a cohort of Zambian CLHIV presenting with new-onset seizure. MethodsIn this prospective cohort study, participants were recruited at the University Teaching Hospital in Lusaka, Zambia. Various clinical and demographic characteristics were obtained. Computed tomography (CT), magnetic resonance imaging (MRI), or both were obtained during admission or shortly after discharge. If both studies were available, MRI data was used. Two neuroradiologists interpreted images using REDCap-based NeuroInterp, a tool that quantifies brain imaging findings. Age-dependent neuropsychologic assessments were administered. ResultsNineteen of 39 (49%) children had a brain MRI, 16 of 39 (41%) had CT, and four of 39 (10%) had both. Mean age was 6.8 years (S.D. = 4.8). Children with advanced HIV disease had higher odds of atrophy (odds ration [OR] 7.2, 95% confidence interval [CI] 1.1 to 48.3). Focal abnormalities were less likely in children receiving antiretroviral therapy (ART) (OR 0.22, 95% CI 0.05 to 1.0). Children with neurocognitive impairment were more likely to have atrophy (OR 8.4, 95% CI 1.3 to 55.4) and less likely to have focal abnormalities (OR 0.2, 95% CI 0.03 to 0.9). ConclusionsFocal brain abnormalities on MRI were less likely in CLHIV on ART. Brain atrophy was the most common imaging abnormality, which was linked to severe neurocognitive impairment.

Prevention of Drug Resistant Epilepsy and Developmental Epileptic Encephalopathy: Preventative Vigabatrin Treatment in Tuberous Sclerosis Complex and the Case for Fenfluramine Treatment of Children with Newly Diagnosed Dravet Syndrome

Tuberous sclerosis complex (TSC) is caused by mutations of hamartin (TSC1) or tuberin (TSC2) resulting in disinhibition of the mTOR pathway of cellular proliferation and differentiation and severe neurocognitive impairment, intractable epilepsy and tumors. Epilepsy develops in ~90% folllowed by drug-resistant epilepsy (DRE). Recently, prevention of DRE and developmental encephalopathy was shown to be possible in TSC using early administration of vigabatrin. For the first time, medical treatment successfully prevented epilepsy and reduced neurocognitive and behavioural co-morbidities. The crucial difference between the preventive and standard treatment groups was the timing of treatment initiation, not the type of the intervention. This paradigm can be extended to patients with other genetic or acquired conditions, including Dravet Syndrome (DS), a severe developmental epileptic encephalopathy (DEE) with DRE and high mortality, due to a de novo mutation of the gene SCN1A which codes for the sodium channel protein <em>a</em> subunit Na<sub>v</sub>1.1. Infants usually develop normally until their first seizure, commonly between 2-15 months. This is followed by DRE and developmental regression. Randomized controlled trials (RCTs) of adjunctive fenfluramine treatment in DS reduced median convulsive seizure frequency by 55.7% over placebo at 0.7 mg/kg/day. 50% of children had 75% seizure frequency reduction, 8% had convulsive seizure freedom versus 0% with placebo, and 18% had only one convulsive seizure versus 0% with placebo. Other pivotal studies showed similar results and efficacy was sustained in for <3 years. Fenfluramine is now a first-line therapy for DS. Given the existence of a remarkably effective treatment fenfluramine for Dravet, preventive therapy presents itself as a natural extension for its application. We hypothesize that not only may seizure outcomes such as time to second seizure and evolution to DRE be positively impacted, but moreover, protective effects on mortality and cognitive outcomes may also be seen.

Severe Sepsis During Treatment for Childhood Leukemia and Sequelae Among Adult Survivors

Children undergoing treatment for leukemia are at increased risk of severe sepsis, a dysregulated immune response to infection leading to acute organ dysfunction. As cancer survivors, they face a high burden of long-term adverse effects. The association between sepsis during anticancer therapy and long-term organ dysfunction in adult survivors of childhood cancer has not been examined. To determine whether severe sepsis during therapy for leukemia in childhood is associated with subsequent chronic health conditions in adult survivors. This cohort study included 644 adult survivors of childhood leukemia who were diagnosed between January 1, 1985, and July 19, 2010, and participated in the St Jude Lifetime Cohort Study. Participants were excluded if they received hematopoietic cell transplant or had relapsed leukemia. Data collection ended June 30, 2017. Data were analyzed from July 1, 2020, to January 5, 2024. Severe sepsis episodes, defined according to consensus criteria as septic shock, acute respiratory distress syndrome, or multiorgan dysfunction associated with infection occurring during anticancer therapy, were abstracted by medical record review for all participants. Common Terminology Criteria for Adverse Events-defined chronic health condition outcomes were independently abstracted. Associations between sepsis and cumulative incidence of chronic health conditions (eg, cardiovascular, pulmonary, kidney, neurological, and neurocognitive outcomes) were compared by adjusted hazard ratios from Cox proportional hazards logistic regression. Inverse propensity score weighting was used to adjust for potential confounders, including age, year of diagnosis, and leukemia type. The study sample consisted of 644 adult survivors of pediatric leukemia (329 women [51.1%] and 315 men [48.9%]; including 56 with a history of acute myeloid leukemia and 585 with a history of acute lymphoblastic leukemia) who were most recently evaluated at a median age of 24.7 (IQR, 21.2-28.3) years at a median time after leukemia diagnosis of 17.3 (IQR, 13.7-21.9) years. Severe sepsis during treatment of acute childhood leukemia occurred in 46 participants (7.1%). Participants who experienced severe sepsis during treatment were more likely to develop moderate to severe neurocognitive impairment (29 of 46 [63.0%] vs 310 of 598 [51.8%]; adjusted hazard ratio, 1.86 [95% CI, 1.61-2.16]; P < .001) significantly affecting attention, executive function, memory and visuospatial domains. Sepsis was not associated with long-term risk of cardiovascular, pulmonary, kidney, or neurological chronic health conditions. In this cohort study of long-term outcomes in survivors of pediatric leukemia, severe sepsis during anticancer therapy for leukemia was associated with a selectively increased risk for development of serious neurocognitive sequelae. Efforts to reduce the effects of anticancer therapy on long-term function and quality of life in survivors might include prevention of severe sepsis during therapy and early detection or amelioration of neurocognitive deficits in survivors of sepsis.

Mechanisms of HIV-mediated blood-brain barrier compromise and leukocyte transmigration under the current antiretroviral era

HIV-associated neurological compromise is observed in more than half of all people with HIV (PWH), even under antiretroviral therapy (ART). The mechanism has been associated with the early transmigration of HIV-infected monocytes across the BBB in a CCL2 and HIV replication-dependent manner. However, the mechanisms of chronic brain damage are unknown. We demonstrate that all PWH under ART have elevated circulating ATP levels that correlate with the onset of cognitive impairment even in the absence of a circulating virus. Serum ATP levels found in PWH with the most severe neurocognitive impairment trigger the transcellular migration of HIV-infected leukocytes across the BBB in a JAM-A and LFA-1-dependent manner. We propose that targeting transcellular leukocyte transmigration could reduce or prevent the devastating consequences of HIV within the brains of PWH under ART.

The role of TSC1 and TSC2 proteins in neuronal axons.

Tuberous Sclerosis Complex 1 and 2 proteins, TSC1 and TSC2 respectively, participate in a multiprotein complex with a crucial role for the proper development and function of the nervous system. This complex primarily acts as an inhibitor of the mechanistic target of rapamycin (mTOR) kinase, and mutations in either TSC1 or TSC2 cause a neurodevelopmental disorder called Tuberous Sclerosis Complex (TSC). Neurological manifestations of TSC include brain lesions, epilepsy, autism, and intellectual disability. On the cellular level, the TSC/mTOR signaling axis regulates multiple anabolic and catabolic processes, but it is not clear how these processes contribute to specific neurologic phenotypes. Hence, several studies have aimed to elucidate the role of this signaling pathway in neurons. Of particular interest are axons, as axonal defects are associated with severe neurocognitive impairments. Here, we review findings regarding the role of the TSC1/2 protein complex in axons. Specifically, we will discuss how TSC1/2 canonical and non-canonical functions contribute to the formation and integrity of axonal structure and function.

A Comprehensive Analysis of Stunting Syndrome in Children in Developing Countries: A Comprehensive Review

Abstract Stunting in children is recognized as the best overall indicator of children’s well-being. It is also the most prevalent form of malnutrition in children and accurately reflects the inequalities prevalent in the society. According to the 2019 World Bank report, the prevalence of stunted children in India is 38%, the second highest in Southeast Asia. On a priority basis, a target has been fixed to reduce the burden of stunting by 40% by 2025. Stunting may be viewed as “stunting syndrome” in view of its multifactorial nature and several pathological changes demonstrating linear growth retardation in early childhood. Linear growth failure serves as an indicator of many associated pathological disorders such as enhanced morbidity and mortality, reduced cognitive and neurodevelopmental potential, reduced physical growth potential, and an increased risk of chronic and metabolic diseases in childhood. Practically, stunting is a cyclical process where women who were stunted in childhood tend to give birth to low birth weight babies who later become stunted creating an intergenerational cycle of difficult-to-interrupt poverty and reduced human capital. These severe irreversible physical and neurocognitive impairments associated with stunting are accepted as a major global health priority. Hence, the mechanism of linear growth faltering needs to be understood, and short-, medium-, and long-term consequences are to be identified and addressed early.

A Narrative Review of the Many Psychiatric Manifestations of Neurosyphilis: The Great Imitator.

Neurosyphilis is an infection of the central nervous system caused by the spirochete, Treponema pallidum. New syphilis infections have been increasing around the world each year. This disease was much of a concern in the pre-penicillin era, where when left untreated many cases progressed to tertiary syphilis which can commonly manifest as neurosyphilis. Of particular interest, neurosyphilis has been linked to masquerading itself as various psychiatric conditions. This narrative review focuses on exploring psychiatric manifestations of neurosyphilis as well as the importance of screening in psychiatric settings and clinicians maintaining high clinical suspicion of the disease. A systematic search was conducted for published articles from 2003 to 2023 using PubMed, EMBASE, and Google Scholar. A total of 66 articles met the criteria and were used for detailed analysis, where psychiatric manifestations and clinical progression of patients were discussed in detail. Psychiatric manifestations that were explored include dementia, delirium, depression, mania, personality changes, and psychosis. One of the most common manifestations of neurosyphilis appears to be severe neurocognitive impairment. There are also rare psychiatric conditions neurosyphilis mimics that have been described in literature such as Capgras syndrome and Geschwind syndrome. A narrative review of the literature revealed a low level of clinical awareness of neurosyphilis as a possible etiology of various psychiatric disorders. This resulted in delayed or inaccurate diagnosis and consequently delayed initiation of adequate treatment. Considering that many psychiatric manifestations of neurosyphilis are reversible with proper treatment, it is imperative to implement routine screening for syphilis among psychiatric patients.

Hypothyroidism in Saudi Arabia: review article

Thyroid hormone is necessary for the healthy development of the nervous system and adequate growth in the first several years of life. The pituitary gland regulates T3 and T4 levels through a feedback mechanism in healthy individuals. One of the most frequent worldwide causes of severe neurocognitive impairment and avoidable mental retardation is congenital hypothyroidism (CH). The incidence of CH was previously thought to be 1:3,000-4,000 live births, however, recent evidence indicated an upward trend. Thus, this review aimed to study the hypothyroidism trends in Saudi Arabia. Several factors could influence the occurrence of hypothyroidism, including age, sex, and other regional considerations. According to the Kingdom of Saudi Arabia, 15.5% of non-endocrine females with a body mass index of 20 or higher had hypothyroidism. Research has revealed a strong link between thyroid disorders and diabetes. According to studies, there is a direct link between high thyroid-stimulating hormone levels and coronary artery disease (CAD), making hypothyroidism a risk factor for CAD. Further, many studies added information demonstrating that hypothyroidism during pregnancy increases the risk of both maternal and newborn outcomes. To offer more precise information about the prevalence and effects of hypothyroidism, a population-based cohort study is required.

Hypothyroidism in Saudi Arabia: a review article

Thyroid hormone is necessary for the healthy development of the nervous system and adequate growth in the first several years of life. The pituitary gland regulates T3 and T4 levels through a feedback mechanism in healthy individuals. One of the most frequent worldwide causes of severe neurocognitive impairment and avoidable mental retardation is congenital hypothyroidism (CH). The incidence of CH was previously thought to be 1:3000–4000 live births, however, recent evidence indicated an upward trend. Thus, this review aimed to study the hypothyroidism trends in Saudi Arabia. Several factors could influence the occurrence of hypothyroidism, including age, sex, and other regional considerations. According to the Kingdom of Saudi Arabia (KSA), 15.5% of non-endocrine females with a BMI of 20 or higher had hypothyroidism. Research has revealed a strong link between thyroid disorders and diabetes. According to studies, there is a direct link between high TSH levels and coronary artery disease (CAD), making hypothyroidism a risk factor for CAD. Further, many studies added information demonstrating that hypothyroidism during pregnancy increases the risk of both maternal and newborn outcomes. To offer more precise information about the prevalence and effects of hypothyroidism, a population-based cohort study is required.

A Rationale and Approach to the Development of Specific Treatments for HIV Associated Neurocognitive Impairment.

Neurocognitive impairment (NCI) associated with HIV infection of the brain impacts a large proportion of people with HIV (PWH) regardless of antiretroviral therapy (ART). While the number of PWH and severe NCI has dropped considerably with the introduction of ART, the sole use of ART is not sufficient to prevent or arrest NCI in many PWH. As the HIV field continues to investigate cure strategies, adjunctive therapies are greatly needed. HIV imaging, cerebrospinal fluid, and pathological studies point to the presence of continual inflammation, and the presence of HIV RNA, DNA, and proteins in the brain despite ART. Clinical trials exploring potential adjunctive therapeutics for the treatment of HIV NCI over the last few decades have had limited success. Ideally, future research and development of novel compounds need to address both the HIV replication and neuroinflammation associated with HIV infection in the brain. Brain mononuclear phagocytes (MPs) are the primary instigators of inflammation and HIV protein expression; therefore, adjunctive treatments that act on MPs, such as immunomodulating agents, look promising. In this review, we will highlight recent developments of innovative therapies and discuss future approaches for HIV NCI treatment.

Neurocognitive trajectories and their clinical implications in first-episode schizophrenia after one year of antipsychotic treatment

Neurocognitive impairment is a core feature of schizophrenia, and patients with first-episode schizophrenia (FES) are optimal candidates for cognitive remediation, but we do not know enough about the incidence, severity and longitudinal changes in neurocognitive impairment in those with FES. This study aimed to assess the neurocognitive trajectories of patients with FES and to compare the clinical and functional outcomes among those with different trajectories. A total of 562 untreated patients with FES completed a neurocognitive test battery and psychopathological and functional assessment. A total of 373 patients attended the follow-up. Group-based trajectory modelling (GBTM) was applied to identify neurocognitive trajectories. Analysis of variance and chi-square tests were conducted to compare demographic characteristics, multiple neurocognitive domains, and clinical and functional outcomes among the different subgroups. We identified three neurocognitive subgroups: preserved (n = 133), mildly to moderately impaired (n = 187) and severely impaired (n = 53). Neurocognitive function in the two impaired subgroups improved within a year but failed to reach the normal level. The processing speed followed trajectories similar to those of overall cognition. The three subgroups did not significantly differ in antipsychotic usage or clinical remission rate. The severely impaired subgroup had poorer functional outcomes than the preserved subgroup, but the mildly to moderately impaired subgroup did not. Patients with FES followed distinct neurocognitive trajectories during the first year of treatment. Patients with severe neurocognitive impairment have poorer functional outcomes, which require and are more likely to benefit from cognitive remediation. Processing speeding is a potential indicator for screening overall cognition.

The effect of pediatric central nervous system tumors on identity in young adult survivors: a project REACH study.

Of all childhood cancers, adult survivors of pediatric central nervous system (CNS) tumors are at the highest risk for late mortality as well as neurocognitive, physical, and psychosocial late effects. Their identity with cancer survivorship, the relationship of their identity to health outcomes, and how their identity differs from other childhood cancer survivors is poorly understood. A total of 127 young adults previously treated for pediatric CNS tumors enrolled in Project REACH, a locally-treated childhood cancer survivor cohort. Participants completed self-report measures on the effects of cancer on identity, someone who had cancer, victim and survivor identity, frequency of thoughts of diagnosis, and health outcomes. The majority of participants identified as a survivor (83%). Survivor identity was linked to diagnosis and treatment but not health outcomes. A minority (9%) endorsed a victim identity, and they were more likely to have poorer mental health (p = 0.03) and depression (p = 0.04) than non-victims. Participants who reported a stronger effect of cancer on their identity also had poorer mental health (p = 0.005). A higher frequency of diagnosis-related thoughts was associated with significantly poorer mental health (p < 0.001), more severe anxiety (p = 0.008), depression (p < 0.001), and neurocognitive impairments (p < 0.01). Those who experienced relapse, radiation, and/or chemotherapy were more likely to identify as someone who had cancer, independent of diagnosis. Our findings suggest the relationships previously reported between identity and sociodemographic, treatment, and health outcomes after adult and pediatric non-CNS cancers cannot be generalized to pediatric CNS tumors. Understanding the unique features of how this population identifies is important for patient-centered care.

Impairment of EEG functional connectivity in dementia during recognition of emotional facial expression

AbstractBackgroundThe performance of facial expression recognition is affected both in neurocognitive disorders and in healthy elderly. Emotional content processing is expected to be adversely affected in dementia and as well in Parkinson's disease patients. The present study aims to compare the impaired facial expression recognition between different types of dementia patients, functional connectivity changes in patients with mild cognitive impairment, and patients with dementia were investigated by event‐related EEG‐coherence.Method25 Healthy elderly controls (HC), 25 Mild Cognitive Impairment patients (MCI), 25 patients with Alzheimer's disease (AD), 15 patients with Parkinson's disease with Mild Cognitive Impairment (PDMCI), and 16 patients with Parkinson's disease Dementia (PDD) were included in the study. EEG was recorded while angry, happy, and neutral facial expressions were presented. The artifacts were rejected by using Independent‐Component‐Analysis and Current‐Source‐Density. Magnitude‐squared coherence values of theta (4‐7Hz, 50‐400ms) responses were calculated. Inter‐hemispheric and intra‐hemispheric (frontal and central centered) pairs of F3, F4, C3, C4, T7, T8, Tp7, Tp8, P3, P4, O1, O2 channels were used. Two separate inter and intra hemispheric repeated‐measures‐ANOVA models were used for group comparisons.ResultThere were no group differences for intra‐hemispheric comparisons, but GroupXLocation comparison (p=.040) was significant, HE and MCI groups had higher coherence values in central‐ temporal, central‐ temporoparietal, and central‐ occipital connections compared to PDMCI, PDD, and AD patient groups (Figure 1). FaceXGroup (p=.009) interaction was significant for inter‐hemispheric coherence values, HC and MCI groups had higher interhemispheric coherence values than the PDMCI, PDD, and AD, especially during recognition of "angry" facial expression.ConclusionThe connectivity between the central and posterior regions increased with emotional face content; this increase seems to be preserved in MCI. On the other hand, it wasn't maintained in patients with more severe neurocognitive impairment; PDMCI, PDD, and AD groups had reduced central‐posterior connectivity and interhemispheric connectivity during the facial expression recognition paradigm. The decrease in inter and intra‐connectivity in the posterior regions is consistent with behavioral scores and may indicate neural losses as a phenomenon.

Advances in the Experimental Models of HIV-Associated Neurological Disorders.

Involvement of the central nervous system (CNS) in HIV-1 infection is commonly associated with neurological disorders and cognitive impairment, commonly referred to as HIV-associated neurocognitive disorders (HAND). Severe and progressive neurocognitive impairment is rarely observed in the post-cART era; however, asymptomatic and mild neurocognitive disorders still exist, despite viral suppression. Additionally, comorbid conditions can also contribute to the pathogenesis of HAND. In this review, we summarize the characterization of HAND, factors contributing, and the functional impairments in both preclinical and clinical models. Specifically, we also discuss recent advances in the animal models of HAND and in in vitro cultures and the potential role of drugs of abuse in this model system of HAND. Potential peripheral biomarkers associated with HAND are also discussed. Overall, this review identifies some of the recent advances in the field of HAND in cell culture studies, animal models, clinical findings, and the limitations of each model system, which can play a key role in developing novel therapeutics in the field.

Doing less, accomplishing more for childhood acute lymphoblastic leukaemia (ALL).

With survival rates of childhood acute lymphoblastic leukaemia (ALL) reaching 90%, the inevitable question is, can we do less? Risk-stratified ALL therapy has led to a low (10%) cumulative risk of relapse (CIR), leading some to question the value of routine, scheduled follow-up and blood counts. In a population-based ALL study from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, Jensen et al1 reported that scheduled follow-up diagnosed only 49% of relapses. Surprisingly, relapses diagnosed during scheduled visits did not fare better (5-year overall survival 63% compared to 72% for relapses detected by extra visits; hazard ratio 0·95). The authors concluded that after completing ALL therapy, scheduled visits yielded no extra benefit. However, this conclusion should be interpreted with caution. Jensen et al. excluded those who underwent haematopoietic stem cell transplantation (HSCT). Also excluded were 262 of 600 (44%) cases of relapses that had occurred during therapy. Patients who were post-HSCT or with relapsed leukaemia had a significantly higher risk of relapse and complications. While Jensen et al. studied only the most feared complications, that is relapse and secondary malignancies, scheduled visits enabled screening for potential severe chronic health conditions (CHCs) and school coping issues. Why did patients, who were diagnosed with relapse during scheduled visits, counter-intuitively, have poorer outcomes? We suggest that they had poorer outcomes because they had significantly higher risk factors.1 Specifically, their median time to relapse was signficantly shorter at 39 months (vs 45 months; P = 0·009). In addition, they had an increased incidence of isolated bone marrow relapse (P = 0·02). Thus, scheduled visits picked up higher risk relapses, which was, in fact, advantageous. To diagnose one subclinical relapse, Jensen et al. calculated that as many as 1269 blood tests had to be done.1 This calculation remained theoretical and biased; all scheduled patients diagnosed with symptoms and signs of relapse were excluded. Such exclusion unnecessarily disadvantaged against scheduled visits. In fact, all patients had scheduled visits; extra visits were additional. Equally important, 58 of 130 (45%) patients who were diagnosed with relapse during extra visits suffered symptoms for >2 weeks. Such delays in diagnosis were of equal concern. After more than 2 years of treatment, the value of a scheduled visit goes beyond just diagnosing relapse alone. The Children’s Cancer Survivor Study2 reported that severe CHCs occurred in 21% of survivors of ALL. However, in risk-stratified standard risk (SR) patients, these severe CHCs were reduced to 11%. Yet, despite this reduction, compared to their siblings, ALL SR survivors experienced increased severe CHC [relative risk (RR) 1·9]. Compared to the general population, this increase in CHC was not associated with increased mortality. In four groups of ALL survivors: (1) relapsed ALL; (2) SCT; (3) cranial or total body irradiation; and (4) high-risk patients, an increased risk of severe CHC and neurocognitive impairment remained.2 We have reported that ALL survivors, especially those treated with cranial radiotherapy, had increased chronic inflammation and accelerated ageing.3 Arguably, to better manage severe CHC, these patients need more, not fewer, scheduled visits and care. For decades, the key concern of both doctors and patients is relapse. Relapse can be catastrophic; it means a resistant disease requiring more intensive therapies with increased morbidity and mortality. Recently, cell-based therapy such as chimeric antigen receptor T-cell therapy against CD19 (CAR-T CD19) cured 50% of B-lymphoblastic leukaemia in second relapse.4 With more effective therapy, relapse may be salvageable. To, carefully, do less and not lose hard-fought gains, we need to choose who can be safely followed up less frequently. From the minimal residual disease-stratified Malaysia-Singapore ALL 2003 experience,5 after completing therapy, the lowest risk patients (Malaysia-Singapore 2003 SR) had only 1·7% CIR (Table I). Similarly, after completing NOPHO ALL 2008 therapy,1 the CIR was only 3·4%. The choice is clear: low-risk ALL patients, treated using reduced intensity protocols without cranial radiotherapy, can be followed less. The authors thank Dr Edwynn Chiew and Mr Chen ZW for providing the updated data on MS2003. All the authors contributed to the writing of the paper. Yeoh AE received speaker fee from Amgen (2020). The other authors have no conflicts of interest.

Prevalence of Severe Neurocognitive Impairment and Its Association with Socio-Demographics and Functionality Among Ugandan Older Persons: A Hospital-Based Study.

BackgroundThe prevalence of neurocognitive disorders, especially dementia, is rising due to an increase in longevity. Early detection and diagnosis of neurocognitive impairments are important for early interventions and appropriate management of reversible causes, especially by the primary health workers. However, this study aimed to determine the prevalence and associated factors of severe neurocognitive impairment among elderly persons attending a tertiary hospital in Uganda.MethodsThis cross-sectional survey was conducted in a Ugandan hospital setting, where older adults go for treatment for their chronic health problems. Following the inclusion criteria, interviews were conducted, where information about socio-demographics was collected, whereas neurocognitive impairment and functionality were assessed by Mini-Mental State Examination and Barthel Index, respectively. Chi-square test, Pearson correlation test, and logistic regression were performed to determine the factors associated with severe neurocognitive impairment.ResultsA total of 507 elderly persons aged 60 years and above were enrolled in this study (mean age 68.62 ±7.95 years), and the prevalence of severe neurocognitive impairment was 28.01%. Advanced age, female gender, lower education level, and functional dependency were significantly associated with severe neurocognitive impairment.ConclusionSevere neurocognitive impairment is prevalent among Ugandan hospital attending elderlies with functional dependency. This suggests a need to routinely screen cognitive disorders among older persons who visit the healthcare facilities with other physical complaints to enable early detection and treatment of reversible causes of neurocognitive impairment, such as depression and delirium to enable better functionality.

Neurocognitive dysfunction among type 2 diabetes patients attending primary health care in Jeddah, Saudi Arabia.

Context:Identification of modifiable risk factors of neurocognitive dysfunction (NCDs) that would help in preventing neurocognitive dysfunction by means of appropriate measures.Objectives:The study aims to provide an insight into the extent and cofactors ofNCDs among Saudi type II diabetes (T2DM) patients at the primary care level.Settings and Design:A cross-sectional study was conducted at five randomly selected primary health care centers (PHCCs) of Jeddah, Saudi Arabia.Subject and Methods:T2DM patients above 40 years, who were followed for T2DM diagnosed ≥ 1 year ago were recruited. The Arabic version of the Mini-Mental State Evaluation (MMSE) was used for screening NCDs, using education-adjusted cut-offs.Statistical Analysis Used:Sociodemographic, diabetes-related, and other clinical and lifestyle factors were analyzed as cofactors of NCDs.Results:The study included 236 T2DM patients, who had mean ± SD age of 60.29 ± 9.45 years. The majority (61.0%) were female, and mean ± SD duration of T2DM was 14.1 ± 8.4 years (range = 1–45 years). The prevalence of NCDs was 35.2% (95% CI = 29.1%, 41.6%), and 5.1% of the participants had MMSE scores ≤ 10 indicating severe neurocognitive impairment. The congruence of significant sociodemographic factors delineated a high-risk profile, and multivariate regression analysis showed female gender, low educational level, longer duration of diabetes, geriatric age at T2DM diagnosis, inadequate glycemic control, and sedentary lifestyle as the independent risk factors for NCDs.Conclusions:The population of middle-aged and older T2DM patients is highly exposed to NCDs, with the great contribution of other comorbidities and higher risk incurred by older, lowly educated females with long diabetes duration. Further improvements should be achieved to enhance the care offered to diabetic patients by improving glycemic control, screening for comorbidities, and early detection of neurocognitive decline.

Entire duration of active psychosis and neurocognitive performance in first-episode non-affective psychosis.

To explore if the entire duration of active psychosis (DAP) is related to neurocognitive performance at baseline and at 3-year follow-up in patients with first episode psychosis (FEP). DAP was estimated for 481 FEP patients. A neuropsychological battery was administered to measure neurocognitive specific domains, and a global indicator of neurocognitive impairment (global deficits score, GDS) was calculated. According to the DAP quartiles, four subgroups were formed, and these were compared. In addition, a logistic regression analysis was carried out to predict neurocognitive impairment at 3-year follow-up. FEP patients with the longest DAP (more than 18.36 months) presented a more severe global neurocognitive impairment evidenced in their GDS, both at baseline (F=5.53; p˂ .01) and at 3-year follow-up (F=4.16; p˂ .01). Moreover, a subgroup of participants with DAP between 7.40 and 18.36 months showed a specific attentional decline over the 3-year follow-up (F=3.089; p˂ .05).The logistic regression model showed that sex (Wald=7.29, p < .010), premorbid adjustment (Wald=7.24, p < .010), attention (Wald=12.10, p < .001), verbal memory (Wald=16.29, p < .001) and visual memory (Wald=9.41, p < .010) were significant predictors of neurocognitive impairment 3 years after the FEP. The variables composing the DAP were not significant predictors in this model. DAP seems to be related to global neurocognitive impairment in FEP patients. These findings contribute in several ways to our understanding of the effects of active psychosis on the brain, and provide the basis for future research.