Neuroimaging of Cryptococcal Meningitis in Patients without Human Immunodeficiency Virus: Data from a Multi-Center Cohort Study.

BACKGROUND: A clearer understanding is needed about the use of brain MRI in non-HIV patients with cryptococcal meningitis. METHODS: Cerebral CT and MRI were studied in 62 patients in a multicenter study of cryptococcal meningitis in non-HIV patients. CT was performed in 51 and MRI in 44. MRI results are reported for the images read at NIH for 29 of the 44 patients. CT reports obtained from the original REDCap database were added to calculate the incidence of normal findings. RESULTS: CTs were read as normal in 24 of 51 (47%), MRIs were normal in 10% (three of 29). The most characteristic lesions of cryptococcal meningitis on MRI were small basal ganglia lesions representing dilated perivascular spaces in 24% and basal ganglia lesions with restricted diffusion (infarcts) in 38%. In the 18 patients who received contrast, contrast-enhancing lesions, likely representing masses of cryptococci and inflammatory cells, were found in the basal ganglia in 22% and elsewhere in the brain in 22%. Meningeal enhancement was seen in 56%, ependymal enhancement in 24%, and choroid plexus enhancement in 11%. Hydrocephalus was found in five (18%), though increased intacranial pressure was not detected. Suboptimal imaging (n = 6), lack of contrast administration (n = 11) and lack of follow-up, however, markedly limited the accurate assessment of abnormalities in multiple cases. CONCLUSION: MRI characteristics of non-HIV cryptococcal meningitis include hydrocephalus, meningeal and ependymal enhancement and basal ganglia lesions. Optimal imaging is, however, necessary to maximize the diagnostic and prognostic usefulness of MRI.

Adoption of newly FDA-approved targeted immunomodulatory therapies by dermatologists: a cross-sectional analysis of Medicare Part D claims from 2013 to 2018.

Although targeted immunomodulatory medications are increasingly utilized for inflammatory skin conditions like plaque psoriasis, little is known of the trends in the adoption of newly Federal Drug Administration (FDA)-approved immunomodulators by dermatologists. We performed a retrospective, cross-sectional analysis of Medicare Part D Prescriber datasets to identify dermatologists filing Medicare prescription claims for immunomodulatory drugs FDA-approved for plaque psoriasis between 2013 and 2018. Differences in dermatologist characteristics were determined between dermatologists prescribing a psoriasis treatment within two years of its FDA approval, "early adopters" and non-prescriber dermatologists over the same time period. Biologics approved for psoriasis from 2013 to 2018 included certolizumab pegol, secukinumab, brodalumab, ixekizumab, guselkumab, and apremilast. Early adopter dermatologists (n = 783) accounted for 5% of all Medicare Part D prescribing dermatologists. Early adopters were more likely to be male, in practice longer, and had a greater number of average annual beneficiaries than dermatologists who did not. Only six (< 1%) early adopters practiced in a small town or rural areas. We believe these data show that the adoption of novel biologic treatments for psoriasis by dermatologists to Medicare beneficiaries may be associated with clinician experience and practice volume. Additionally, we identified low absolute numbers of dermatologists prescribing biologics overall in non-metropolitan areas, which may represent delayed access to novel psoriasis treatments for many Medicare beneficiaries.

U.S. Trends in Registration for Medical Cannabis and Reasons for Use From 2016 to 2020 : An Observational Study.

BACKGROUND: Cannabis policy liberalization has increased cannabis availability for medical or recreational purposes. Up-to-date trends in medical cannabis licensure can inform clinical policy and care. OBJECTIVE: To describe recent trends in medical cannabis licensure in the United States. DESIGN: Ecological study with repeated measures. SETTING: State registry data via state reports and data requests on medical cannabis licensure from 2016 to 2020. PARTICIPANTS: Medical cannabis patients (persons with medical cannabis licenses) in the United States. MEASUREMENTS: Total patient volume, patients per 10 000 of total population, and patient-reported qualifying conditions (that is, symptoms or conditions qualifying patients for licensure)-including whether these symptoms align with current therapeutic evidence of cannabis-cannabinoid efficacy. RESULTS: In 2020, 26 states and Washington, DC reported patient numbers, and 19 states reported patient-reported qualifying conditions. Total enrolled patients increased approximately 4.5-fold from 678 408 in 2016 to 2 974 433 in 2020. Patients per 10 000 total population generally increased from 2016 to 2020, most dramatically in Oklahoma (927.1 patients per 10 000 population). However, enrollment increased in states without recreational legalization (that is, medical-only states), whereas enrollment decreased in 5 of 7 with recreational legalization (that is, recreational states). In 2020, 68.2% of patient-reported qualifying conditions had substantial or conclusive evidence of therapeutic value versus 84.6% in 2016. Chronic pain was the most common patient-reported qualifying condition in 2020 (60.6%), followed by posttraumatic stress disorder (10.6%). LIMITATION: Missing state data; lack of rationale for discontinuing medical cannabis licensure. CONCLUSION: Enrollment in medical cannabis programs approximately increased 4.5-fold from 2016 to 2020, although enrollment decreased in recreational states. Use for conditions or symptoms without a strong evidence basis increased from 15.4% (2016) to 31.8% (2020). Thoughtful regulatory and clinical strategies are needed to effectively manage this rapidly changing landscape. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse of the National Institutes of Health.

Persulfate-containing consumer products in the US market.

BACKGROUND: Persulfate compounds are reactive oxidative agents increasingly recognized as contact allergens. OBJECTIVES: The aim of this study was to identify common consumer products containing persulfate compounds in the US market. METHODS: Five publicly accessible online ingredient repositories and searches of two large online retailers were used to identify persulfate-containing consumer products. RESULTS: We identified persulfates in 23 hair colouring products, 11 denture cleansers, 8 pool/hot-tub products, 3 paints, and 3 cleaning products. CONCLUSIONS: Clinicians assessing contact dermatitis should be aware of three primary categories of consumer products that contain persulfates: denture cleansers, hair colouring products, and nonchlorine hot-tub and pool shock.

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.

Quality of life of HIV-negative, previously healthy individuals following cryptococcal meningoencephalitis.

The morbidity and mortality of cryptococcal meningoencephalitis (CM) in previously healthy, HIV-negative individuals is increasingly recognized. We administered a healthcare associated quality of life (QOL) survey to the largest longitudinally followed cohort of these patients in the United States. We identified moderate or severe self-reported impairment in at least one QOL domain in 61% of subjects at least one year following diagnosis. Self-reported cognitive impairment was noted in 52% and sleep disturbance was noted in 55%. This is the first comprehensive study of cross-sectional long-term QOL in previously healthy patients following cryptococcal infection.

Central Nervous System Histoplasma-Associated Post-infectious Inflammatory Response Syndrome (Histo-PIIRS).

We present a case of central nervous system (CNS) histoplasmosis in a previously healthy adult with hepatitis C (HCV) presenting with neurological symptoms refractory to antifungal therapy and ventriculoperitoneal (VP) shunting 4 months after initial diagnosis. Persistent symptoms were thought to be inflammatory rather than infectious given negative cerebrospinal fluid (CSF) and serum fungal antigens. The patient promptly improved after initiation of corticosteroid therapy. Elevated CSF cytokines and regional enhancement on brain MRI resolved with corticosteroid treatment. This is the first case of Histoplasma-associated post-infectious inflammatory response syndrome (Histo-PIIRS) documented by CSF cytokine reduction in response to corticosteroid therapy.

Outcomes in Previously Healthy Cryptococcal Meningoencephalitis Patients Treated With Pulse Taper Corticosteroids for Post-infectious Inflammatory Syndrome.

BACKGROUND: Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. METHODS: Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. RESULTS: The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P < .0003), which was accompanied by improvements in CSF glucose, white blood cell (WBC) count, protein, cellular and soluble inflammatory markers 1 week after receiving corticosteroids (CS) (P < .003). All patients with papilledema and visual field deficits also exhibited improvement (P < .0005). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement. Brain MRI showed significant improvement of radiological findings (P = .001). CSF cultures remained negative. CONCLUSIONS: PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.

Cerebrovascular Disease in Children Perinatally Infected With Human Immunodeficiency Virus in Zambia.

BACKGROUND: High rates of cerebrovascular disease (CVD) have previously been described in pediatric human immunodeficiency virus (HIV). However, little is known about pediatric CVD in the era of antiretroviral therapy or about the contribution of CVD to HIV-associated neurocognitive disorders. METHODS: We completed a neuroimaging substudy of the HIV-Associated Neurocognitive Disorders in Zambia study, a prospective cohort study of neurocognitive complications of pediatric HIV. Brain magnetic resonance imaging (1.5 T) was acquired for 34 HIV+ children on antiretroviral therapy and 17 HIV-exposed uninfected children (aged eight to 17 years). Demographics, medical history, neurological examination, and neuropsychologic testing results were collected. Two neuroradiologists, unaware of HIV status and clinical course, read the scans. RESULTS: CVD was identified in seven of 34 children with HIV (HIV+ CVD+) and no HIV-exposed uninfected children (21% vs 0%, P = 0.05). Three participants had white matter changes suggestive of small vessel disease, four had infarcts, and two had evidence of intracranial artery stenosis. Age of antiretroviral therapy initiation and exposure to protease inhibitors or efavirenz was not significantly different between children with and without CVD. HIV+ CVD+ children had significantly worse scores on a summary measure of cognition than the HIV+ CVD- group (NPZ8 score -0.57 vs 0.33, P = 0.04). CONCLUSIONS: This study demonstrates high rates of CVD in children with HIV despite antiretroviral therapy, and worse cognitive performance in children with CVD. Longitudinal studies are necessary to determine the mechanisms and incidence of new-onset CVD in children with HIV.

Text messaging and lottery incentive to improve colorectal cancer screening outreach at a community health center: A randomized controlled trial.

Efforts to boost colorectal cancer (CRC) screening rates in underserved populations have been limited by effectiveness and scalability. We evaluate the impact of adding a lottery-based financial incentive to a text messaging program that asks patients to opt-in to receive mailed fecal immunochemical testing (FIT). This is a two-arm pragmatic randomized controlled trial at a community health center in Southwest Philadelphia from April to July 2017. We included CRC screening-eligible patients between ages 50-74 years who had a mobile phone, active health insurance, and at least one visit to the clinic in the past 12 months. Patients received a text message about CRC screening with the opportunity to opt-in to receive mailed FIT. They were randomized 1:1 to the following: (1) text messaging outreach alone (text), or (2) text messaging with lottery for a 1-in-5 chance of winning $100 after FIT completion (text + lottery). The primary outcome was the percentage of patients completing the mailed FIT within 3 months of initial outreach. 281 patients were included in the intent-to-treat analysis. The FIT completion rate was 12.1% (95% CI, 6.7%-17.5%) in the text message arm and 12.1% (95% CI, 6.7%-17.5%) in the lottery arm, with no statistical difference between arms. The majority of post-intervention interview respondents found text messaging to be acceptable and convenient. Opt-in text messaging is a feasible option to promote the uptake of mailed FIT screening, but the addition of a lottery-based incentive did not improve completion rates. Trial Registration: clinicaltrials.gov (NCT03072095).

Neurocysticercosis Among Zambian Children and Adolescents With Human Immunodeficiency Virus: A Geographic Information Systems Approach.

BACKGROUND: Neurocysticercosis is the most common parasitic infection of the brain and a leading cause of epilepsy in resource-limited settings. Although neurocysticercosis and human immunodeficiency virus coinfections have commonly been reported, there are few data on how they interact. As part of an observational study of human immunodeficiency virus and cognition in Lusaka, Zambia, we identified a cluster of subjects with neurocysticercosis. We hypothesized that the neighborhood of residence may be an important factor driving clustering of neurocysticercosis and used a geographic information systems approach to investigate this association. METHODS: A total of 34 subjects with human immunodeficiency virus and 13 subjects without human immunodeficiency virus (aged eight to 17 years) enrolled in the HIV-Associated Neurocognitive Disorders in Zambia study, had magnetic resonance imaging of the brain performed, and were evaluated for neurocysticercosis. Quantitative geographic information systems was utilized to investigate the relationship between neighborhood of residence, HIV, and neurocysticercosis. RESULTS: Three of 34 subjects with human immunodeficiency virus (8.82%) and one of 13 controls were found to have neurocysticercosis. Geographic cluster analysis demonstrated that all subjects with neurocysticercosis were clustered in two adjacent neighborhoods (Chawama and Kanyama) with lower rates of piped water (Chawama: 22.8%, Kanyama: 26.7%) and flush toilets (Chawama: 14.0%, Kanyama: 14.0%) than the surrounding neighborhoods. CONCLUSION: We describe a cluster of patients with both neurocysticercosis and human immunodeficiency virus in Lusaka. Cases of neurocysticercosis clustered in neighborhoods with low rates of piped water and limited access to flush toilets. Geographic information systems may be a useful approach for studying the relationship between human immunodeficiency virus and neurocysticercosis. Larger studies are necessary to further investigate this association.

Brain Magnetic Resonance Imaging Findings Associated With Cognitive Impairment in Children and Adolescents With Human Immunodeficiency Virus in Zambia.

BACKGROUND: Cognitive impairment is common in children and adolescents with human immunodeficiency virus (HIV). Brain magnetic resonance imaging (MRI) is a potentially useful tool to investigate the pathophysiology of HIV-associated cognitive impairment and may serve as a biomarker in future clinical trials. There are few published data on brain imaging in children with HIV in sub-Saharan Africa. METHODS: Thirty-four perinatally infected subjects with HIV and age-matched HIV-exposed uninfected controls between the ages nine and 17 years were recruited from the Pediatric Center of Excellence in Lusaka, Zambia, as part of the HIV-associated Neurocognitive Disorders in Zambia study. Brain MRI sequences were acquired, and clinical and volumetric assessments were performed. Subjects underwent a comprehensive neuropsychologic battery, and cognitive impairment status was classified using a global deficit score approach. Regression models were used to evaluate relationships between MRI findings and cognitive function. RESULTS: We identified cerebrovascular disease in seven of 34 subjects with HIV compared with zero of 17 controls (21% vs 0%, P = 0.04). We also identified decreased total brain volumes (1036 vs 1162 cm3, P = 0.03) and decreased cortical thickness in the right temporal lobes (3.12 vs 3.29 mm; P = 0.01) and right fusiform gyri (3.10 vs 3.25 mm; P = 0.02) of HIV-infected subjects with cognitive impairment. CONCLUSIONS: These findings support the hypothesis that brain volumes may be useful biomarkers for cognitive outcomes in children with HIV. Further studies are necessary to investigate mechanisms of cerebrovascular disease and volume loss in children with HIV.

Progressive divisions of multipotent neural progenitors generate late-born chandelier cells in the neocortex.

Diverse γ-aminobutyric acid (GABA)-ergic interneurons provide different modes of inhibition to support circuit operation in the neocortex. However, the cellular and molecular mechanisms underlying the systematic generation of assorted neocortical interneurons remain largely unclear. Here we show that NKX2.1-expressing radial glial progenitors (RGPs) in the mouse embryonic ventral telencephalon divide progressively to generate distinct groups of interneurons, which occupy the neocortex in a time-dependent, early inside-out and late outside-in, manner. Notably, the late-born chandelier cells, one of the morphologically and physiologically highly distinguishable GABAergic interneurons, arise reliably from continuously dividing RGPs that produce non-chandelier cells initially. Selective removal of Partition defective 3, an evolutionarily conserved cell polarity protein, impairs RGP asymmetric cell division, resulting in premature depletion of RGPs towards the late embryonic stages and a consequent loss of chandelier cells. These results suggest that consecutive asymmetric divisions of multipotent RGPs generate diverse neocortical interneurons in a progressive manner.

Internal Cholinergic Regulation of Learning and Recall in a Model of Olfactory Processing.

In the olfactory system, cholinergic modulation has been associated with contrast modulation and changes in receptive fields in the olfactory bulb, as well the learning of odor associations in olfactory cortex. Computational modeling and behavioral studies suggest that cholinergic modulation could improve sensory processing and learning while preventing pro-active interference when task demands are high. However, how sensory inputs and/or learning regulate incoming modulation has not yet been elucidated. We here use a computational model of the olfactory bulb, piriform cortex (PC) and horizontal limb of the diagonal band of Broca (HDB) to explore how olfactory learning could regulate cholinergic inputs to the system in a closed feedback loop. In our model, the novelty of an odor is reflected in firing rates and sparseness of cortical neurons in response to that odor and these firing rates can directly regulate learning in the system by modifying cholinergic inputs to the system. In the model, cholinergic neurons reduce their firing in response to familiar odors-reducing plasticity in the PC, but increase their firing in response to novel odor-increasing PC plasticity. Recordings from HDB neurons in awake behaving rats reflect predictions from the model by showing that a subset of neurons decrease their firing as an odor becomes familiar.

Basal forebrain dynamics during nonassociative and associative olfactory learning.

Cholinergic and GABAergic projections from the horizontal diagonal band (HDB) and medial preoptic area (MCPO) of the basal forebrain to the olfactory system are associated with odor discrimination and odor learning, as well as modulation of neural responses in olfactory structures. Whereas pharmacological and lesion studies give insights into the functional role of these modulatory inputs on a slow timescale, the response dynamics of neurons in the HDB/MCPO during olfactory behaviors have not been investigated. In this study we examined how these neurons respond during two olfactory behaviors: spontaneous investigation of odorants and odor-reward association learning. We observe rich heterogeneity in the response dynamics of individual HDB/MCPO neurons, with a substantial fraction of neurons exhibiting task-related modulation. HDB/MCPO neurons show both rapid and transient responses during bouts of odor investigation and slow, long-lasting modulation of overall response rate based on behavioral demands. Specifically, baseline rates were higher during the acquisition phase of an odor-reward association than during spontaneous investigation or the recall phase of an odor reward association. Our results suggest that modulatory projections from the HDB/MCPO are poised to influence olfactory processing on multiple timescales, from hundreds of milliseconds to minutes, and are therefore capable of rapidly setting olfactory network dynamics during odor processing and learning.