A molecularly integrated grade for meningioma

BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.     

Factors Contributing to Delay in Driving Licensure Among U.S. High School Students and Young Adults

PurposeMore teens delay in driving licensure (DDL). It is conceivable they miss Graduated Driver Licensing (GDL) safety benefits. We assessed prevalence, disparities, and factors associated with DDL among emerging adults.MethodsData used were from all seven waves (W1–7) of the NEXT Generation Health Study (W1 in 10th grade [2009–2010]). The outcome variable was DDL (long-DDL [delayed >2 years], intermediate-DDL [delayed 1–2 years] versus no-DDL), defined as participants receiving driver licensure ≥1 year after initial eligibility. Independent variables included sex, urbanicity, race/ethnicity, family structure, parental education, family affluence, parental monitoring knowledge, parent perceived importance of alcohol nonuse, and social media use. Logistic regressions were conducted.ResultsOf 2,525 participants eligible for licensure, 887 (38.9%) reported intermediate-DDL and 1,078 (30.1%) long-DDL. Latinos (adjusted odds ratio [AOR] = 2.5 vs. whites) and those with lower affluence (AOR = 2.5 vs. high) had higher odds of intermediate-DDL. Latinos (AOR = 4.5 vs. whites), blacks (AOR = 2.3 vs. whites), those with single parent (AOR = 1.7 vs. both biological parents), whose parents’ education was high school or less (AOR = 3.7 vs. bachelor+) and some college (AOR = 2.0 vs. bachelor+) levels, and those with lower affluence (AOR = 4.4 vs. high) had higher odds of long-DDL. Higher mother’s monitoring knowledge (AOR = .6) was associated with lower odds of long-DDL, but not intermediate-DDL.ConclusionsSome teens that DDL “age out” of protections afforded to them by GDL driver restrictions. Minority race/ethnicity, socioeconomic status, urbanicity, and parenting factors contribute to DDL. Further study of these factors and their individual/collective contributions to DDL is needed to understand potential unintended consequences of GDL, particularly in more vulnerable youth.     

Vitamin A serostatus and heterosexual transmission of HIV: case-control study in Tanzania and review of the evidence

Results from a randomized clinical trial suggested that vitamin A/beta-carotene supplementation to HIV-1-infected women during pregnancy and lactation may increase the risk of vertical transmission. Limited information is available on the potential role of vitamin A on heterosexual HIV transmission. This is a relevant question in many resource-limited settings where both vitamin A deficiency and HIV infection are highly prevalent. We conducted a case-control study (34 cases and 38 controls) nested within a cohort of HIV-negative women attending family planning clinics in Tanzania, to examine whether low serum concentrations at baseline were associated with the risk of seroconversion. There was not a significant association (OR = 2.14, 95% C I = 0.54, 8.45). In light of these and previous results, we conclude that there is not enough evidence yet to suggest a causal association between vitamin A and heterosexual transmission.     

Mechanism of voltage sensing in Ca2+- and voltage-activated K+ (BK) channels

In neurosecretion, allosteric communication between voltage sensors and Ca²⁺ binding in BK channels is crucially involved in damping excitatory stimuli. Nevertheless, the voltage-sensing mechanism of BK channels is still under debate. Here, based on gating current measurements, we demonstrate that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. Significantly, the energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). Molecular dynamics simulations and proton transport experiments in the hyperpolarization-activated R210H mutant suggest that the electric field drops off within a narrow septum whose boundaries are defined by the gating charges. Unlike Kv channels, the charge movement in BK appears to be limited to a small displacement of the guanidinium moieties of R210 and R213, without significant movement of the S4.

Excitable tissues accomplish their signaling functions thanks in part to the interplay of several voltage-sensitive ion channels (1–6). Hence, to understand these processes, it is crucial to establish how voltage-sensitive ion channels sense changes in the electric field across the membrane, an issue that has been a matter of extensive study and intense debate for decades. The most widely accepted mechanism proposes the existence of voltage-sensor domains (VSDs), modules that undergo two or more discrete conformational states in response to changes in the membrane voltage. The simplest model considers two states: active (A), which promotes pore opening, and resting (R), which promotes channel closing. To accomplish its function, VSDs contain voltage-sensitive particles, which move in response to changes in the electric field. This movement triggers the interconversion between the two discrete conformational states. These voltage-sensing particles are typically the guanidine groups of arginine residues within the S4 transmembrane segment, which undergo a combination of rotational, translational, and tilting movement in response to changes in membrane voltage (7–14).The large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels have a wide distribution in mammalian tissues (15–18), where they participate in a diversity of physiological processes. Their malfunction is often related to diverse pathological conditions (19, 20). BK channel open probability is independently regulated by membrane depolarization and intracellular Ca²⁺ concentration (21, 22), each stimulus being detected by specialized modules. Like other voltage-sensitive K⁺ (Kv) channels, BK is an homotetramer in which each of its α subunits consists of a pore domain (PD; S5-S6 transmembrane segments), a voltage-sensing domain (VSD; S1–S4 transmembrane segments) containing a positively charged S4, and a cytosolic C-terminal regulatory domain, which contains the Ca²⁺-binding sites (23, 24). Also, like some members of other K⁺ channel families (25, 26), the VSD and PD of BK are non–domain swapped (23, 24). BK channels display some distinctive structural and functional features: Despite sharing the selectivity filter sequence with Kv channels, BK unitary conductance and selectivity are exquisitely high (27–30). The BK α subunit has an additional transmembrane segment S0 [therefore, its N terminus faces the extracellular medium (31)], and the voltage sensitivity in BK channels is significantly lower than that of Kv channels, presumably because of their lower number of gating charges (32).Although thoroughly studied, research into BK VSD and its voltage dependence has faced several technical obstacles. The relatively small gating charge per channel (32) and the large conductance of the BK pore makes isolating of the gating currents from the ionic currents a tough experimental challenge. In addition, because mutations of VSD residues can produce very large shifts in both the gating charge-voltage (Q(V)) and the conductance-voltage G(V)) relationships (33), it is necessary to use extreme voltages to accurately measure the voltage dependence of some mutants. Consequently, the identification of BK gating charges has been addressed by using indirect approaches (33, 34). The combination of electrophysiology measurements and kinetic modeling suggests a decentralized VSD in the BK channel, where four charged residues (D153 and R167 in S2, D186 in S3, and R213 in S4) act as voltage sensor particles (33). A recent report of the atomistic cryo-electron microscopy (cryo-EM) structures of the human BK channel and its homolog in Aplysia californica (AcSlo) revealed minor structural differences between the VSD in both the Ca²⁺-bound (open pore) and the Ca²⁺-unbound (closed pore) conformations (23, 24, 35). This result can be explained if the conformational changes of the BK VSD upon activation are small compared to those that occur during the activation of other channels, such as HCN channels (12–14).In this study, we identified voltage-sensing particles in the BK channel by using a direct functional approach, involving gating of current measurements and analysis of the Q(V) curves spanning 800 mV in the voltage axis. Systematic neutralization of the individual charged residues in the VSD (S1–S4) revealed that only the neutralization of two arginines in S4 (R210 and R213) changed the voltage dependence of the Q(V) curves. Neutralization of other VSD charges point to roles in tuning of the half-activation voltage of the VSD and its allosteric coupling with the PD. Molecular dynamics (MD) simulations based on the cryo-EM structures of the human BK channel (35) as templates suggested that R210 and R213 lie in a very narrow septum separating intra- and extracellular water-filled vestibules. This interpretation is consistent with the robust hyperpolarization-activated proton currents generated when R210 is mutated to the protonable amino acid histidine. Overall, our results point to a unique and distinctive mode of activation in BK: In contrast to Kv channels, where positive charges move one by one through a charge transfer center (absent in BK channels) that spans the entire electric field (36, 37), charge movement in BK channels is limited to the small displacement of R210 and R213, which itself constitutes a narrow septum where the electric field drops.     

Ovarian clear cell carcinoma arising in a large endometrioma — A case report with pathological correlation and literature review

Endometriosis-associated ovarian cancer represents the most common form of malignancy associated with this benign disease. It has a better prognosis than most types of ovarian cancer, with endometrioid adenocarcinoma and clear cell carcinoma as the main histological types. Clinical presentation is usually nonspecific and tumor biomarkers can be misleading, since they can also be elevated in the presence of benign ovarian endometriosis. We report a case of a 52-year-old woman with known ovarian and deep pelvic endometriosis, who developed ovarian clear cell carcinoma within a large endometrioma. The imaging findings highlight the key role of magnetic resonance imaging in detecting suspicious features such as loss of the “T2 shading” sign, loss of high T1 signal of an endometrioma, or the presence of mural nodules. Early detection of these malignancies is fundamental for adequate surgical treatment and overall outcome.     

Allen Cognitive Level Screen for the classification of subjects treated for addiction

Introduction The Cognitive Disabilities Model (CDM) is an occupational approach that can allow the classification of the functional-cognitive abilities of persons with addictions. The objective of the study was to explore the applicability of the ACLS-5 to assess a sample of persons undergoing addiction-rehabilitation treatment. Methods A sample of 232 participants was recruited from an outpatient treatment centre in Madrid (Spain). The ACLS-5, the Montreal Cognitive Assessment (MoCA), and the Prefrontal Symptom Inventory (PSI) were administered. Sociodemographic and addiction-related data were also obtained. Results Half of the sample showed serious deficits in functional cognition, which ultimately could be related to problems in their daily performance. Scores of ACLS-5 showed significant correlations with the severity of addiction, with those obtained with the MoCA, and with attentional symptoms on the PSI scale. Conclusions The data suggest the applicability of the ACLS-5 in assessing the degree of functional cognition in subjects treated for addiction, providing evidence to support ecological validity and facilitating the development of well-targeted cognitive rehabilitation programmes from an occupational perspective. The use of occupational-based instruments to assess the functioning of those with addictions is a requirement of occupational therapy professionals working in this general area.     

Virtual Seminar on Coronavirus 2019 for the US-Mexico Border Region: Building Opportunities for Communication and Collaboration

While the US-Mexico border region has had increasing restrictions due to coronavirus 2019 (COVID-19), the economically and socially integrated region continues to facilitate necessary movement between the two countries. Binational partners representing universities, government, and health delivery worked together to develop a COVID-19 Virtual Seminar for the US-Mexico Border Region, which consisted of weekly sessions in Spanish designed to better facilitate communication and collaborative systems between border states. In total 835 participants registered for the virtual seminar with attendance ranging from 394 in Session 1 to 269 in Session 6. From evaluation surveys (n?=?297), organizers observed a large plurality of healthcare professionals, followed by students, researchers, and government employees. The seminar’s contribution to increasing collaborative and communication systems identified major needs in the region surrounding surveillance and monitoring; increased resources for migrant shelters to control outbreaks; an increase in personal protective equipment; tracking binational cases.

     

Willingness to Self-Collect a Sample for HPV-Based Cervical Cancer Screening in a Well-Screened Cohort: HPV FOCAL Survey Results

Self-collection may provide an opportunity for innovation within population-based human papillomavirus (HPV) cervical cancer screening programs by providing an alternative form of engagement for all individuals. The primary objective was to determine willingness to self-collect a vaginal sample for primary HPV screening and factors that impact willingness in individuals who participated in the Human Papillomavirus For Cervical Cancer (HPV FOCAL) screening trial, a large randomized controlled cervical screening trial. A cross-sectional online survey was distributed between 2017 and 2018 to 13,176 eligible participants exiting the FOCAL trial. Bivariate and multivariable logistic regression assessed factors that influence willingness to self-collect on 4945 respondents. Overall, 52.1% of respondents indicated willingness to self-collect an HPV sample. In multivariable analysis, the odds of willingness to self-collect were significantly higher in participants who agreed that screening with an HPV test instead of a Pap test was acceptable to them (odds ratio (OR): 1.45 (95% confidence interval (CI): 1.15, 1.82), those who indicated that collecting their own HPV sample was acceptable to them (p < 0.001), and those with higher educational ascertainment (OR: 1.31, 95% CI: 1.12, 1.54). The findings offer insight into the intentions to self-collect in those already engaged in screening, and can inform cervical cancer screening programs interested in offering alternative approaches to HPV-based screening.     

Searching for bridges between psychopathology and real-world functioning in first-episode psychosis: A network analysis from the OPTiMiSE trial

BackgroundNetwork analysis has been used to explore the interplay between psychopathology and functioning in psychosis, but no study has used dedicated statistical techniques to focus on the bridge symptoms connecting these domains. The current study aims to estimate the network of depressive, negative, and positive symptoms, general psychopathology, and real-world functioning in people with first-episode schizophrenia or schizophreniform disorder, focusing on bridge nodes.MethodsBaseline data from the OPTiMiSE trial were analyzed. The sample included 446 participants (age 40.0 ± 10.9 years, 70% males). The network was estimated with a Gaussian graphical model, using scores on individual items of the positive and negative syndrome scale (PANSS), the Calgary depression scale for schizophrenia, and the personal and social performance scale. Stability, strength centrality, expected influence (EI), predictability, and bridge centrality statistics were computed. The top 20% scoring nodes on bridge strength were selected as bridge nodes.ResultsNodes from different rating scales assessing similar psychopathological and functioning constructs tended to cluster together in the estimated network. The most central nodes (EI) were Delusions, Emotional Withdrawal, Depression, and Depressed Mood. Bridge nodes included Depression, Conceptual Disorganization, Active Social Avoidance, Delusions, Stereotyped Thinking, Poor Impulse Control, Guilty Feelings, Unusual Thought Content, and Hostility. Most of the bridge nodes belonged to the general psychopathology subscale of the PANSS. Depression (G6) was the bridge node with the highest value.ConclusionsThe current study provides novel insights for understanding the complex phenotype of psychotic disorders and the mechanisms underlying the development and maintenance of comorbidity and functional impairment after psychosis onset.