Synthesis of Bis-Chalcones and Evaluation of Its Effect on Peroxide-Induced Cell Death and Lipopolysaccharide-Induced Cytokine Production.

Plant secondary metabolites are important sources of biologically active compounds with wide pharmacological potentials. Among the different classes, the chalcones form integral pharmacologically active agents. Natural chalcones and bis-chalcones exhibit high antioxidant and anti-inflammatory properties in various experiments. Studies are also underway to explore more biologically active bis-chalcones by chemical synthesis of these compounds. In this study, the effects of six synthetic bis-chalcones were evaluated in intestinal epithelial cells (IEC-6); further, the anti-inflammatory potentials were studied in lipopolysaccharide-induced cytokine production in macrophages. The synthesized bis-chalcones differ from each other first of all by the nature of the aromatic cores (functional group substitution, and their position) and by the size of a central alicycle. The exposure of IEC-6 cells to peroxide radicals reduced the cell viability; however, pre-treatment with the bis-chalcones improved the cell viability in these cells. The mechanism of action was observed to be the increased levels of glutathione and antioxidant enzyme activities. Further, these bis-chalcones also inhibited the LPS-stimulation-induced inflammatory cytokine production in RAW 264.7 macrophages. Overall, the present study indicated the cytoprotective and anti-inflammatory abilities of synthetic bis-chalcones.

Antioxidant, Antimicrobial, Cytotoxicity, and Larvicidal Activities of Selected Synthetic Bis-Chalcones.

Plants are known to have numerous phytochemicals and other secondary metabolites with numerous pharmacological and biological properties. Among the various compounds, polyphenols, flavonoids, anthocyanins, alkaloids, and terpenoids are the predominant ones that have been explored for their biological potential. Among these, chalcones and bis-chalcones are less explored for their biological potential under in vitro experiments, cell culture models, and animal studies. In the present study, we evaluated six synthetic bis-chalcones that were different in terms of their aromatic cores, functional group substitution, and position of substitutions. The results indicated a strong antioxidant property in terms of DPPH and ABTS radical-scavenging potentials and ferric-reducing properties. In addition, compounds 1, 2, and 4 exhibited strong antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella enteritidis. The disc diffusion assay values were indicative of the antibacterial properties of these compounds. Overall, the study indicated the antioxidant and antimicrobial properties of the compounds. Our preliminary studies point to the potential of this class of compounds for further in vivo investigation.

Causes of Pediatric Deaths in Lusaka, Zambia: A Quantitative Geographic Information Systems Approach.

Background: While childhood mortality has been declining in Zambia, it remains high at 58 per 1000 live births. Importantly, many leading causes of mortality in Zambia are preventable. This study was conducted to identify clusters of childhood mortality, causes of death of recently deceased children, barriers to care, and risk factors for mortality in Lusaka, Zambia. Methods: This study was conducted as a prospective cohort study. Family members or lawfully authorized representatives (LARs) were interviewed when they came to pick up death certificates for recently deceased children from Lusaka Children's Hospital. Each interview included a verbal autopsy, determination of the child's location of residence, and collection of demographic information. Demographic data was also collected from a healthy control group. Quantitative Geographic Information Systems was used to visualize mortality and evaluate for clustering. Results: Leading primary causes of death included malnutrition (21%), complications of chronic illnesses (16%), and central nervous system infections (13%), while the leading barriers to care were cost (58%) and difficulties with travel (53%). Compared to controls, recently deceased children came from families with significantly lower incomes (1905 Kwacha vs. 2412 Kwacha, p = 0.03) and were significantly more likely to have a history of malnutrition (16.7% vs. 1.4%, p = 0.005). Mortality was clustered in two high-population density, low-income neighborhoods in Lusaka. Conclusions: Systems to reduce financial barriers to care and improve access to transportation could reduce childhood mortality in Lusaka. The aforementioned neighborhoods are ideal locations for public health interventions or improved healthcare services.

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

BACKGROUND: There 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. METHODS: In 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. RESULTS: Nineteen 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). CONCLUSIONS: Focal 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.

Acetaminophen and Ibuprofen in Pediatric Central Nervous System Malaria: A Randomized Clinical Trial.

Importance: A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae. Objective: To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher. Design, Setting, and Participants: This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023. Intervention: The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher. Main Outcomes and Measures: The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance. Results: Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07). Conclusions and Relevance: This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia. Trial Registration: ClinicalTrials.gov Identifier: NCT03399318.

Early Initiation of Antiretroviral Therapy is Protective Against Seizures in Children With HIV in Zambia: A Prospective Case-Control Study.

BACKGROUND: Seizures are relatively common among children with HIV in low- and middle-income countries and are associated with significant morbidity and mortality. Early treatment with antiretroviral therapy (ART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. METHODS: We conducted a prospective, unmatched case-control study. We enrolled children with new-onset seizure from University Teaching Hospital in Lusaka, Zambia and 2 regional hospitals in rural Zambia. Controls were children with HIV and no history of seizures. Recruitment took place from 2016 to 2019. Early treatment was defined as initiation of ART before 12 months of age, at a CD4 percentage >15% in children aged 12-60 months or a CD4 count >350 cells/mm 3 for children aged 60 months or older. Logistic regression models were used to evaluate the association between potential risk factors and seizures. RESULTS: We identified 73 children with new-onset seizure and compared them with 254 control children with HIV but no seizures. Early treatment with ART was associated with a significant reduction in the odds of seizures [odds ratio (OR) 0.04, 95% confidence interval: 0.02 to 0.09; P < 0.001]. Having an undetectable viral load at the time of enrollment was strongly protective against seizures (OR 0.03, P < 0.001), whereas history of World Health Organization Stage 4 disease (OR 2.2, P = 0.05) or CD4 count <200 cells/mm 3 (OR 3.6, P < 0.001) increased risk of seizures. CONCLUSIONS: Early initiation of ART and successful viral suppression would likely reduce much of the excess seizure burden in children with HIV.

Long-term outcomes after new onset seizure in children living with HIV: A cohort study.

OBJECTIVE: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure. METHODS: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality. RESULTS: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence. SIGNIFICANCE: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures. PLAIN LANGUAGE SUMMARY: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures.

Modulating nanostructure morphology and mesomorphic properties using unsaturation in cardanol-azo benzenes.

Herein, we report the synthesis and self-assembly of a new class of amphiphilic azo dyes derived from a plant-based phenol, cardanol. Analysis of the self-assembly of these new azo derivatives was intriguing, and they exhibit some unique nanostructures, such as bicelles and microgel-like structures, and smectic-type thermotropic mesophases.

The optimal time for endotracheal intubation in subjects with coronavirus disease 2019 pneumonia: A retrospective observational study.

Background: The optimal timing of intubation has been debated among healthcare professionals, current studies do not show any differences between early and late intubation. most studies failed to show any significant difference in clinical outcomes between early or late intubation. Methods: The study was conducted as a retrospective review of subjects with confirmed coronavirus disease 2019 admitted to the Dubai Hospital intensive care unit (ICU). Study variables included time to intubation, duration of supplemental oxygen requirement >15 L/min, and cumulative duration of tachypnea and tachycardia while on the aforementioned oxygen requirement on this oxygen usage level. Each time duration was assessed for correlation with clinical variables including mortality and length of stay in ICU and hospital. Results: Subjects who require endotracheal intubation within 4 h after the start of oxygen >15 L/min have lower survival (P = 0.03). Subjects who have tachypnea on the aforementioned oxygen requirement for 6-19.5 h (P = 0.01) before they require intubation have better survival. No duration of tachycardia has any significant effect on survival. Only the duration of invasive mechanical ventilation (MV) correlated with the hospital length of stay. Conclusions: Subjects who require endotracheal intubation within 4 h after the start of oxygen >15 L/min have lower survival. The optimal time for intubation is after tachypnea of 6 h but before 19.5 h. No duration of tachycardia has any significant effect on survival. Only the duration of invasive MV correlated with the hospital length of stay.

Patient, Provider, and Health Systems Factors Leading to Lumbar Puncture Nonperformance in Zambia: A Qualitative Investigation of the "Tap Gap".

Lumbar puncture (LP) and cerebrospinal fluid (CSF) diagnostics are critical for evaluating central nervous system infections but are often not conducted, resulting in the "Tap Gap." To investigate patient, provider, and health systems factors contributing to the Tap Gap in Zambia, we conducted focus group discussions with adult caregivers of hospitalized inpatients and in-depth interviews with nurses, clinicians, pharmacy workers, and laboratory staff. Transcripts were independently thematically categorized by two investigators using inductive coding. We identified seven patient-related factors: 1) alternative understandings of CSF; 2) alternative information about LPs, including misinformation; 3) mistrust of doctors; 4) consent delays; 5) fear of blame; 6) peer pressure against consent; and 7) association between LP and stigmatized conditions. Four clinician-related factors were identified: 1) limited LP knowledge and expertise, 2) time constraints, 3) delays in LP requests by clinicians, and 4) fear of blame for bad outcomes. Finally, five health systems-related factors were identified: 1) supply shortages, 2) constrained access to neuroimaging, 3) laboratory factors, 4) availability of antimicrobial medications, and 5) cost barriers. Efforts to improve LP uptake must incorporate interventions to increase patient/proxy willingness to consent and improve clinician LP competencies while addressing both upstream and downstream health system factors. Key upstream factors include inconsistently available consumables for performing LPs and lack of neuroimaging. Critical downstream factors include laboratory services that offer poor availability, reliability, and/or timeliness of CSF diagnostics and the reality that medications needed to treat diagnosed infections are often unavailable unless the family has resources to purchase privately.

Synthesis and Liquid Crystalline Properties of Low Molecular Weight Bis- Chalcone Compounds.

AIMS: In this paper, we report on the synthesis and liquid crystalline properties of some low molecular weight bis-chalcone compounds derived from acetone, cyclopentanone and cyclohexanone mesogenic cores. BACKGROUND: Structurally bis-chalcones belong to a broader family of chalcone compounds. Chalcone is a compound that consists of two aromatic rings linked by an unsaturated α, ß-ketone. OBJECTIVE: Liquid crystalline chalcones are prepared by aliphatic chain substituents on two aromatic rings. Chalcones are well studied for their mesomorphic properties. Compared to a large number of chalcone based LCs reported, only a few articles have been published on the mesomorphic properties of bis-chalcone compounds. The target compounds of the present study varied not only in their central core but also in number and position of terminal aliphatic chain substitution-a key structural unit in deciding the liquid crystalline properties of a compound. METHODS: All target compounds were synthesized in good yield by base catalyzed Claisen-Schmidt condensation reaction. Molecular structures were confirmed by FT-IR, 1H NMR, 13C NMR, and mass spectroscopic methods. Liquid crystalline property of these compounds was evaluated using polarizing optical microscopy and differential scanning calorimetry. RESULTS: Although none of the acetone based compounds exhibited mesomorphism, cyclopentanone and cyclohexanone based compounds with octyloxy chain at para position on either side of the dibenzylidine ring stabilized liquid crystalline smectic (SmA and SmC) and nematic (N) phases. The observed structure-liquid crystalline property relationship was explained by structural analysis of molecules using DFT calculations. Considering the inherent photoluminescence nature of the chalcone moiety, a preliminary study was carried out on a selected compound to reveal its fluorescence property. CONCLUSION: Our study brings about an important structure-liquid crystalline property relationship in a relatively unexplored class of bis-chalcone liquid crystals.

Aggressive antipyretics in central nervous system malaria: Study protocol of a randomized-controlled trial assessing antipyretic efficacy and parasite clearance effects (Malaria FEVER study).

BACKGROUND: Malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neuro-disability. Evidence indicates that a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted among children with complicated malaria at substantial risk of brain injury. Previous clinical trials conducted primarily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with central nervous system (CNS) malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5°C) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. METHODS: In this double-blinded, placebo controlled, two-armed clinical trial, we will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children's Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2-11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation randomization either to standard of care for fever management or to prophylactic, scheduled treatment every 6 hours for 72 hours with dual antipyretic therapies using acetaminophen and ibuprofen. Assignment to treatment groups will be with 1:1 allocation using blocked randomization. The primary outcome will be maximum temperature in the 72 hours after enrolment. Secondary outcomes include parasite clearance as determined by quantitative Histidine Rich Protein II and seizures through 72 hours after enrolment. DISCUSSION: This clinical trial seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic using two antipyretics and prophylactic administration and will elucidate the impact of antipyretics on parasite clearance and acute symptomatic seizures. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted.

The effect of caring for critically ill patients with COVID-19 acute respiratory distress syndrome in undesignated intensive care unit wardson mortality and length of hospital stay.

INTRODUCTION: COVID-19 has caused 4 million deaths as of 24 August 2021. A significant number of patients were admitted to undesignated ICU areas before transfer to a desig-nated ICU owing to the unavailability of ICU beds. We aim to compare the mortality and length of stay of patients in these 2 areas. MATERIAL AND METHODS: We retrospectively studied all critically ill patients with COVID-19 pneumonia who were admitted to Dubai hospital between 1 January 2020 and 30 June 2020. Patients who transferred to wards other than designated ICU constitute cases, while those who were admitted directly to designated ICUs constitute controls. The demographics, clinical parameters, and treatment profile of these patients were recorded and compared. Mortality and length of stay were calculated. RESULTS: The sample includes 239 subjects (admitted to an undesignated ICU ward [n = 107] and directly admitted to a designated ICU ward [n = 132]). Patients admitted to an undesignated ICU had extra transfers between wards and had more days on MV (median [IQR] 18 (19) vs. 11 (14); P = 0.001), greater length of stay in the ICU (median [IQR]) 21.5 (19) vs. 15 (14); P = 0.001), and greater length of stay in hospital (median [IQR] 32 (28) vs. 21 (26); P = 0.001). Multiple logistic regression analysis showed that patients treated at an undesignated ICU have better survival (odds of death for patients cared for at an undesignated ICU was 0.347 with CI 0.178-0.676; P = 0.002). Multiple linear regression analysis also showed that patients treated at an undesignated ICU had longer stay - 4.2 days, CI 1.3-7.13, P = 0.004). CONCLUSIONS: Admission to an undesignated ICU impacts mortality and length of ICU and hospital stay.

Antiproliferative, apoptosis-inducing activity and molecular docking studies of sydnones compounds.

Objective: To evaluate the antiproliferative and apoptosis inducing activity of different sydnones on cancer cell lines and their interaction with cancer proteins by molecular docking studies. Material and Methods: Antiproliferative activity was carried out by MTT assay and apoptosis inducing activity was performed by DAPI and Annexin V and propidium iodide staining. Molecular docking studies were performed using AutoDock Tools 1.5.6. Pharmacokinetics properties like ADME and toxicity were analysed by pkCSM web server. Result: In this study, four new sydnone compounds 3-(4-nonylbiphenyl-4'-yl) sydnone (MC-182), 3-(4-propylbiphenyl-4'-yl) sydnone (MC-454), 3-(4-hexylbiphenyl-4'-yl) sydnone (MC-433), and 3-(4-methylbiphenyl-4'-yl) sydnone (MC-431) were screened for antiproliferative and apoptotic effect against BT-474 (human breast cancer), HeLa (human cervical cancer) and Jurkat (human myeloid leukemia) Mostly, all the sydnone compounds exhibited decent antiproliferative effectiveness, but compound MC-431, MC-433, and MC-454 showed more antiproliferative activity (IC50 1.71, 10.09 and 2.87 µM against BT-474, Hela and Jurkat cell line, respectively). The changes of morphological characteristics of cancer cells determined by staining techniques indicate the apoptotic cell death. The molecular docking and interaction studies were carried out between sydnones with cancer proteins (epidermal growth factor domain receptor tyrosine kinase [EGF-TK], tumor necrosis factor-alpha [TNF-α] and Caspase3. Among all four sydnone molecules, two compounds MC-454 and MC-431 showed good binding energy with targeted proteins. Drug-like property was predicted by ADME toxicity study. Conclusion: The results indicate sydnone compounds were found to exhibit anticancer activity by inducing apoptosis. The molecular docking study of sydnones with cancer proteins showed a decent interaction affinity. The results of absorption, distribution, metabolism, excretion and toxicity studies by the Insilco approach also proved that MC-454 sydnone showed better In-Vivo administration. Thus, the current research work indicates that these sydnone compounds would be prospective in developing anticancer medicines.

Socioeconomic Status and Cognitive Function in Children With HIV: Evidence From the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) Study.

BACKGROUND: Multiple previous studies have identified a detrimental effect of pediatric HIV on cognitive function. Socioeconomic status (SES) is one of the strongest predictors of cognitive performance and may affect the relationship between HIV and cognition. METHODS: As part of the ongoing HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, a prospective cohort study, we recruited 208 participants with HIV and 208 HIV-exposed uninfected controls, all aged 8-17 years. A standardized questionnaire was administered to assess SES, and all participants had comprehensive neuropsychological testing. An NPZ8 score was derived as a summary measure of cognitive function. Logistic regression and linear regression were used to model the relationship between SES and cognitive function, and mediation analysis was used to identify specific pathways by which SES may affect cognition. RESULTS: Children with HIV performed significantly worse on a composite measure of cognitive function (NPZ8 score -0.19 vs. 0.22, P < 0.001) and were more likely to have cognitive impairment (33% vs. 19%, P = 0.001). Higher SES was associated with reduced risk of cognitive impairment (odds ratio 0.8, 95% confidence interval: 0.75-0.92, P < 0.001) in both groups, with similar effects in children with HIV and HIV-exposed uninfected groups. SES was more strongly correlated with NPZ8 score in children with HIV than in uninfected controls (Pearson's R 0.39 vs. 0.28), but predicted NPZ8 in both groups. Mediation analysis suggested that the effect of SES on cognition was most strongly mediated through malnutrition. CONCLUSIONS: Cognitive function is strongly correlated with SES in children with HIV, suggesting a synergistic effect of HIV and poverty on cognitive function.

Clinical characteristics and outcomes after new-onset seizure among Zambian children with HIV during the antiretroviral therapy era.

OBJECTIVE: This study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new-onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30-day mortality and cause of death are also reported. METHODS: Children living with HIV (CLWHIV) with new-onset seizures were prospectively evaluated at one large urban teaching hospital and two non-urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed. RESULTS: From April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2-10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presenting with multiple recurrent seizures in the 24 hours before admission or in status epilepticus. Although 36 (49%) were on ART at enrollment, only 7 of 36 (19%) were virally suppressed. Seizure etiologies were infectious in over half (54%), with HIV encephalitis, bacterial meningitis, and tuberculous meningitis being the most common. Metabolic causes (19%) included renal failure and hypoglycemia. Structural lesions identified on imaging accounted for 10% of etiologies and included stroke and non-accidental trauma. No etiology could be identified in 12 (16%) children, most of whom died before the completion of clinical investigations. Twenty-two (30%) children died within 30 days of the index seizure. SIGNIFICANCE: Despite widespread ART roll out in Zambia, new-onset seizure in CLWHIV occurs in the setting of advanced, active HIV disease. Seizure severity/burden is high as is early mortality. Enhanced programs to assure early ART initiation, improve adherence, and address ART failure are needed to reduce the burden of neurological injury and premature death in CLWHIV.

Factors Associated with Lumbar Puncture Performance in Zambia.

In much of sub-Saharan Africa, lumbar punctures (LPs) are performed less frequently than indicated. This is often attributed to patient/family refusal; however, other factors have not been systematically evaluated. We investigated predictors of LP performance for a prospective cohort of people with HIV and new-onset seizures at three hospitals in Zambia. We enrolled 257 participants, including 184 (72%) adults and 144 (56%) urban participants. LPs were performed for 65% of adults and 33% of children, and for 69% of urban and 38% of rural participants. In multivariate logistic regression analyses, LP completion was significantly less likely at one rural site and among children compared to adults. The worst WHO HIV disease stage was associated with increased odds of undergoing LP. Low LP completion rates in Zambia are multifactorial and related to health system and provider factors and patient/family preferences. Further research is necessary to understand this complex problem and develop interventions to improve LP uptake.

Neighborhood-Based Socioeconomic Determinants of Cognitive Impairment in Zambian Children With HIV: A Quantitative Geographic Information Systems Approach.

BACKGROUND: Place-based inequalities, such as exposure to violence and access to nutritious food and clean water, may contribute to human immunodeficiency virus (HIV)-associated cognitive impairment. In this study, we investigated neighborhood effects on cognition in children and adolescents with HIV in Lusaka, Zambia. METHODS: We conducted a prospective cohort study of 208 children with perinatally acquired HIV (ages 8-17) and 208 HIV-exposed uninfected controls. Participants underwent neuropsychological testing and interviews assessing socioeconomic status. Geographic regions with clusters of participants with HIV and cognitive impairment were identified using quantitative geographic information systems (QGIS) and SaTScan. Associations between location of residence and cognitive function were evaluated in bivariable and multivariable regression models. Mediation analysis was performed to assess direct and indirect effects of location of the residence on cognitive impairment. RESULTS: Residence in Chawama, one of the poorest neighborhoods in Lusaka, was significantly associated with cognitive impairment in participants with HIV (odds ratio 2.9; P = .005) and remained significant in a multivariable regression model controlling for potential confounders. Mediation analysis found that 46% of the cognitive effects of residence in Chawama were explained by higher rates of malnutrition, lower school attendance, and poorer self-reported health. CONCLUSIONS: Place-based socioeconomic inequality contributes to cognitive impairment in Zambian children and adolescents with HIV. Neighborhood effects may be mediated by concentrated poverty, malnutrition, limited access to education and health care, and other yet unknown environmental factors that may be potentially modifiable.

Light-driven reversible handedness inversion in self-organized helical superstructures.

We report here a fast-photon-mode reversible handedness inversion of a self-organized helical superstructure (i.e., a cholesteric liquid crystal phase) using photoisomerizable chiral cyclic dopants. The two light-driven cyclic azobenzenophanes with axial chirality show photochemically reversible trans to cis isomerization in solution without undergoing thermal or photoinduced racemization. As chiral inducing agents, they exhibit good solubility, high helical twisting power, and a large change in helical twisting power due to photoisomerization in three commercially available, structurally different achiral liquid crystal hosts. Therefore, we were able to reversibly tune the reflection colors from blue to near-IR by light irradiation from the induced helical superstructure. More interestingly, the different switching states of the two chiral cyclic dopants were found to be able to induce a helical superstructure of opposite handedness. In order to unambiguously determine the helical switching, we employed a new method that allowed us to directly determine the handedness of the long-pitched self-organized cholesteric phase.

A light-controlled molecular brake with complete ON-OFF rotation.

A light-controlled molecular machine based on cyclic azobenzenophanes consisting of a dioxynaphthalene rotating unit and a photoisomerizable dioxyazobenzene unit bridged by methylene spacers is reported. In compounds 1 and 2, 1,5- and 2,6-dioxynaphthalene moieties, respectively, are linked to p-dioxyazobenzene by different methylene spacers (n=2 in 1a and 2; n=3 in 1b), whereas a 1,5-dioxynaphthalene moiety is bonded to m-dioxyazobenzene by bismethylene spacers in 3. In 1b and 2, the naphthalene ring can rotate freely in both the trans and cis states at room temperature. The rotation speed can be controlled either by photoinduced reversible trans-cis (E-Z) isomerization of the azobenzene or by keeping the system at low temperature, as is evident from its NMR spectra. Furthermore, for the first time, we demonstrate a light-controlled molecular brake, wherein the rotation of the naphthalene moiety through the cyclophane is completely OFF in the trans isomer of compound 3 due to its smaller cavity size. Such restricted rotation imparts planar chirality to the molecule, and the corresponding enantiomers could be resolved by chiral HPLC. However, the rotation of the naphthalene moiety is rendered ON in the cis isomer due to its increased cavity size, and it is manifested experimentally by the racemization of the separated enantiomers by photoinduced E-Z isomerization.