Silencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression loss to a PD patient cohort. However, it is still unknown whether Rit2 loss itself impacts DA neuron function and/or viability. Here we report that conditional Rit2 silencing in mouse DA neurons drove motor dysfunction that occurred earlier in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreased DA release, striatal DA content, phenotypic DAergic markers, DA neurons, and DAergic terminals, with increased pSer129-alpha synuclein and pSer935-LRRK2 expression. These results provide clear evidence that Rit2 loss is causal for SNc cell death and motor dysfunction, and reveal key sex-specific differences in the response to Rit2 loss.

Triiodide Attacks the Organic Cation in Hybrid Lead Halide Perovskites: Mechanism and Suppression.

Molecular I2 can be produced from iodide-based lead perovskites under thermal stress; triiodide, I3 - , is formed from this I2 and I- . Triiodide attacks protic cation MA+ - or FA+ -based lead halide perovskites (MA+ , methylammonium; FA+ , formamidinium) as explicated through solution-based nuclear magnetic resonance (NMR) studies: triiodide has strong hydrogen-bonding affinity for MA+ or FA+ , which leads to their deprotonation and perovskite decomposition. Triiodide is a catalyst for this decomposition that can be obviated through perovskite surface treatment with thiol reducing agents. In contrast to methods using thiol incorporation into perovskite precursor solutions, no penetration of the thiol into the bulk perovskite is observed, yet its surface application stabilizes the perovskite against triiodide-mediated thermal stress. Thiol applied to the interface between FAPbI3 and Spiro-OMeTAD ("Spiro") prevents oxidized iodine species penetration into Spiro and thus preserves its hole-transport efficacy. Surface-applied thiol affects the perovskite work function; it ameliorates hole injection into the Spiro overlayer, thus improving device performance. It helps to increase interfacial adhesion ("wetting"): fewer voids are observed at the Spiro/perovskite interface if thiols are applied. Perovskite solar cells (PSCs) incorporating interfacial thiol treatment maintain over 80% of their initial power conversion efficiency (PCE) after 300 h of 85 °C thermal stress.

Rit2 silencing in dopamine neurons drives a progressive Parkinsonian phenotype.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression anomalies to a PD patient cohort. However, it is still unknown whether Rit2 loss itself is causative for PD or PD-like symptoms. Here we report that conditional Rit2 silencing in mouse DA neurons drove a progressive motor dysfunction that was more rapid in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreases in DA release, striatal DA content, phenotypic DAergic markers, and a loss of DA neurons, with increased pSer129-alpha synuclein expression. These results provide the first evidence that Rit2 loss is causal for SNc cell death and a PD-like phenotype, and reveal key sex-specific differences in the response to Rit2 loss.

Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression loss to a PD patient cohort. However, it is still unknown whether Rit2 loss itself is causative for PD or PD-like symptoms. Here we report that conditional Rit2 silencing in mouse DA neurons drove motor dysfunction that occurred earlier in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreased DA release, striatal DA content, phenotypic DAergic markers, DA neurons, and DAergic terminals, with increased pSer129-alpha synuclein and pSer935-LRRK2 expression. These results provide the first evidence that Rit2 loss is causal for SNc cell death and a PD-like phenotype, and reveal key sex-specific differences in the response to Rit2 loss.

Factors impacting parental uptake of COVID-19 vaccination for U.S. Children ages 5-17.

COVID-19 vaccination of U.S. children lags behind adult vaccination, but remains critical in mitigating the pandemic. Using a subset of a nationally representative survey, this study examined factors contributing to parental uptake of COVID-19 vaccine for children ages 12-17 and 5-11, stratified by parental COVID-19 vaccination status. Among vaccinated parents, uptake was higher for 12-17-year-olds (78.6%) than 5-11-year-olds (50.7%); only two unvaccinated parents vaccinated their children. Child influenza vaccination was predictive of uptake for both age groups, while side effect concerns remained significant only for younger children. Although parents were more likely to involve adolescents in vaccine decision-making than younger children, this was not predictive of vaccine uptake. These results highlight the importance of addressing the unique and shared concerns parents have regarding COVID-19 vaccination for children of varying ages. Future work should further explore adolescent/child perspectives of involvement in COVID-19 vaccination decision-making to support developmentally appropriate involvement.

Presynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor function.

Extracellular dopamine (DA) levels are constrained by the presynaptic DA transporter (DAT), a major psychostimulant target. Despite its necessity for DA neurotransmission, DAT regulation in situ is poorly understood, and it is unknown whether regulated DAT trafficking impacts dopaminergic signaling and/or behaviors. Leveraging chemogenetics and conditional gene silencing, we found that activating presynaptic Gq-coupled receptors, either hM3Dq or mGlu5, drove rapid biphasic DAT membrane trafficking in ex vivo striatal slices, with region-specific differences between ventral and dorsal striata. DAT insertion required D2 DA autoreceptors and intact retromer, whereas DAT retrieval required PKC activation and Rit2. Ex vivo voltammetric studies revealed that DAT trafficking impacts DA clearance. Furthermore, dopaminergic mGlu5 silencing elevated DAT surface expression and abolished motor learning, which was rescued by inhibiting DAT with a subthreshold CE-158 dose. We discovered that presynaptic DAT trafficking is complex, multimodal, and region specific, and for the first time, we identified cell autonomous mechanisms that govern presynaptic DAT tone. Importantly, the findings are consistent with a role for regulated DAT trafficking in DA clearance and motor function.

Burst Spinal Cord Stimulation in the Management of Chronic Pain: Current Perspectives.

Over the last several decades, opioid diversion, misuse, and over-prescription have run rampant in the United States. Spinal cord stimulation (SCS) has been FDA approved for treatment for a primary indication of neuropathic limb pain that is resistant to more conservative medical therapy. The disorders qualified for treatment include neuropathic, post-surgical, post-amputation, osteodegenerative, and pain related to vascular disease. Some of the most frequently cited conditions for treatment of SCS include failed back surgery syndrome, complex regional pain syndrome (CRPS) Type I and Type II, and post-herpetic neuralgias. Developments in SCS systems have led to the differentiation between the delivered electromechanical waveform patterns, including tonic, burst, and high-frequency. Burst SCS mitigates traditional paresthesia due to expedited action potential and offers improved pain relief. Burst SCS has been shown in available studies to be non-inferior to the traditional SCS, which can cause pain paresthesia in patients who already have chronic pain. Burst SCS does not seem to cause or need the paresthesia seen in traditional SCS, making SCS not tolerable to patients. Moreover, some studies suggest that burst SCS may decrease opioid consumption in patients with chronic pain. This can make burst SCS an extremely useful tool in the battle against chronic pain and the raging opioid epidemic. As of now, more research needs to be performed to further delineate the effectiveness and long-term safety of this device.

Quantitative Hole Mobility Simulation and Validation in Substituted Acenes.

Knowledge of the full phonon spectrum is essential to accurately calculate the dynamic disorder (σ) and hole mobility (µh) in organic semiconductors (OSCs). However, most vibrational spectroscopy techniques under-measure the phonons, thus limiting the phonon validation. Here, we measure and model the full phonon spectrum using multiple spectroscopic techniques and predict µh using σ from only the Γ-point and the full Brillouin zone (FBZ). We find that only inelastic neutron scattering (INS) provides validation of all phonon modes, and that σ in a set of small molecule semiconductors can be miscalculated by up to 28% when comparing Γ-point against FBZ calculations. A subsequent mode analysis shows that many modes contribute to σ and that no single mode dominates. Our results demonstrate the importance of a thoroughly validated phonon calculation, and a need to develop design rules considering the full spectrum of phonon modes.

Bremelanotide for Treatment of Female Hypoactive Sexual Desire.

Hypoactive sexual desire disorder (HSDD) is a persistent deficiency or absence of sexual fantasies and desire resulting in significant distress or interpersonal difficulty. Women with this disorder may display a lack of motivation for sexual activity, reduced responsiveness to erotic cues, a loss of interest during sexual activity, and avoidance of situations that could lead to sexual activity. The pathophysiology of HSDD is thought to be centered around inhibitory and excitatory hormones, neurotransmitters, and specific brain anatomy. Due to the multifactorial nature of HSDD, treatment can be complex and must attempt to target the biological and psychosocial aspects of the disorder. Bremelanotide is a melanocortin receptor agonist and has been recently approved by the FDA to treat HSDD. Bremelanotide is administered intranasally or as a subcutaneous injection. The recommended dosage of bremelanotide is 1.75 mg injected subcutaneously in the abdomen or thigh at least 45 min before sexual activity. Studies showed improvements in desire, arousal, and orgasm scores when 1.75 mg of bremelanotide was administered before sexual activity compared to a placebo. Bremelanotide is a promising way to treat HSDD.

Anticipated emotional and behavioral responses to ambiguous rejection by a significant other, friend, or acquaintance.

Although there is an extensive literature on interpersonal rejection, individual studies that have examined adults' emotional and behavioral responses to rejection have tended to limit their scope to a specific category of rejector (e.g., acquaintances). As a result, prior research has failed to systematically investigate whether individuals' emotional and behavioral responses to perceived rejection differ as a function of the role of the potential rejector. In the present study, a total of 481 participants read two scenarios describing hypothetical situations in which rejection by a specific individual (i.e., significant other, friend, or acquaintance) was ambiguous. After each scenario, participants rated the extent to which they would be likely to anticipate (a) experiencing various negative emotions (e.g., upset) and (b) engaging in various behavioral responses (i.e., act friendly, retaliate, complain, avoid) to the potential rejector. Overall, the potential of being rejected by another person with whom one has a close and valued relationship (i.e., a significant other and, to a lesser degree, a friend) was associated with heightened negative emotion and a heightened likelihood of engaging in an active response, either prosocial (i.e., act friendly) or antisocial (i.e., retaliate or complain). In contrast, potential rejection by an acquaintance was associated with relatively little negative emotion and relatively little desire to engage the other (i.e., avoid). In sum, the participants' relationship with specific individuals was found to influence both the intensity of their anticipated negative emotional response to ambiguous rejection and the pattern of their anticipated behavioral response to the potential rejectors.

Compendium of causative genes and their encoded proteins for common monogenic disorders.

A compendium is presented of inherited monogenic disorders that have a prevalence of >1:20,000 in the human population, along with their causative genes and encoded proteins. "Simple" monogenic diseases are those for which the clinical features are caused by mutations impacting a single gene, usually in a manner that alters the sequence of the encoded protein. Of course, for a given "monogenic disorder", there is sometimes more than one potential disease gene, mutations in any one of which is sufficient to cause phenotypes of that disorder. Disease-causing mutations for monogenic disorders are usually passed on from generation to generation in a Mendelian fashion, and originate from spontaneous (de novo) germline founder mutations. In the past monogenic disorders have often been written off as targets for drug discovery because they sometimes are assumed to be rare disorders, for which the meager projected financial payoff of drug discovery and development has discouraged investment. However, not all monogenic diseases are rare. Here, we report that that currently available data identifies 72 disorders with a prevalence of at least 1 in 20,000 humans. For each, we tabulate the gene(s) for which mutations cause the spectrum of phenotypes associated with that disorder. We also identify the gene and protein that most commonly causes each disease. 34 of these disorders are caused exclusively by mutations in only a single gene and encoded protein.

Anion Exchange Doping: Tuning Equilibrium to Increase Doping Efficiency in Semiconducting Polymers.

High electron affinity (EA) molecules p-type dope low ionization energy (IE) polymers, resulting in an equilibrium doping level based on the energetic driving force (IE-EA), reorganization energy, and dopant concentration. Anion exchange doping (AED) is a process whereby the dopant anion is exchanged with a stable ion from an electrolyte. We show that the AED level can be predicted using an isotherm equilibrium model. The exchange of the dopant anion (FeCl3-) for a bis(trifluoromethanesulfonamide) (TFSI-) anion in the polymers poly(3-hexylthiophene-2,5-diyl) (P3HT) and poly[3-(2,2-bithien-5-yl)-2,5-bis(2-hexyldecyl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione-6,5-diyl] (PDPP-2T) highlights two cases in which the process is nonspontaneous and spontaneous, respectively. For P3HT, FeCl3 provides a high doping level but an unstable counterion, so exchange results in an air stable counterion with a marginal increase in doping. For PDPP-2T, FeCl3 is a weak dopant, but the exchange of FeCl3- for TFSI- is spontaneous, so the doping level increases by >10× with AED.

Adults' attitudes toward children, adolescents, and adults who are obese and tax-funded programs to combat obesity.

The goals of the present study were to assess (1) adults' patterns of beliefs about and attitudes toward children, adolescents, and adults who are obese and (2) their attitudes toward hypothetical tax-funded programs designed to combat obesity in children, adolescents, and adults. A total of 267 participants, ranging in age from 19 to 88 years old, were recruited through Amazon's Mechanical Turk (MTurk) to participate online in the present study. The participants rated adults who are obese less favorably, and as less malleable, than children or adolescents who are obese. Furthermore, they were less supportive of tax-funded programs designed to combat obesity in adults than children or adolescents. In general, the participants' relatively unfavorable response to adults who are obese appears to be associated with the beliefs that older individuals who are obese are relatively unchangeable and have heightened personal fault for their plight.

Do most premature babies get discharged by the expected date of delivery?

OBJECTIVE: To compare the length of stay (LOS) against the expected date of delivery (EDD) and to describe mortality and LOS outcomes by gestational age (GA) categories over the years. STUDY DESIGN: Healthcare Cost and Utilization Project Kids' Inpatient database discharge records for years 2003, 2006, 2009, 2012, and 2016 were analyzed. For premature infants after inclusion-exclusion, actual, and calculated LOS were compared. Mortality and LOS outcomes were analyzed by GA and years. RESULTS: The majority (99%) of infants >28 weeks were discharged by EDD while, for neonate ≤28 weeks, about three-quarters (75%) of infants were discharged by calculated EDD. LOS is increasing while mortality is decreasing by GA categories in recent years. CONCLUSIONS: This is the largest study of mortality and LOS in the United States. Our study provides evidence-based numbers comparing actual LOS against EDD, which can be used in perinatal settings to counsel parents.

Role of Fault Attributions and Other Factors in Adults' Attitudes Toward Hypothetical Children With an Undesirable Characteristic.

A total of 184 adults read descriptions of six hypothetical children with various undesirable characteristics (i.e., being extremely overweight, extremely aggressive, extremely shy, a poor student, a poor athlete, displaying symptoms of attention deficit hyperactivity disorder). Following each description, the participants were asked to rate how much they disagree or agree that the child, the child's parents, and the child's biological condition (i.e., "something wrong inside the child's body or brain") are at fault for the onset and the perpetuation of the undesirable characteristic. In addition, the participants were asked to rate their attitude toward each child using a 100-point "feeling thermometer." Analyses of the participants' various fault attribution ratings revealed that they tended to agree more strongly that a child's parents and his/her biological condition are at fault for the onset and the perpetuation of the child's undesirable characteristic than is the child him/herself. Despite the participants' reluctance to blame a hypothetical child for his/her undesirable characteristic, regression analyses revealed that, in general, the more they blamed the child for the onset of his/her undesirable characteristic, the more negative their attitude was toward the child. However, the participants' ratings of the extent to which the child's parents or biological condition are at fault for the onset and the perpetuation of the child's undesirable characteristic were not found to be associated with their attitude toward any of the children. Similarities and differences between the present findings and those reported in prior studies involving younger individuals are addressed.

A proposed management algorithm for late-onset efavirenz neurotoxicity.

A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases.

Identification of delirium and dementia in older medical inpatients in Tanzania: A comparison of screening and diagnostic methods.

BACKGROUND: In sub-Saharan Africa, there are no validated screening tools for delirium in older adults. This study assesses clinical utility of two instruments, the IDEA cognitive screen and the Confusion Assessment Method (CAM) for identification of delirium in older adults admitted to medical wards of a tertiary referral hospital in Tanzania. METHOD: The IDEA cognitive screen and CAM were administered to a consecutive cohort of older individuals on admission to Kilimanjaro Christian Medical Centre using a blinded protocol. Consensus diagnosis for delirium was established against DSM-5 criteria and dementia by DSM-IV criteria. RESULTS: Of 507 admission assessments, 95 (18.7%) had DSM-5 delirium and 95 (18.7%) had DSM-IV dementia (33 (6.5%) delirium superimposed on dementia). The CAM and IDEA cognitive screen had very good diagnostic accuracy for delirium (AUROC curve 0.94 and 0.87 respectively). However, a number of participants (10.5% and 16.4% respectively) were unable to complete these screening assessments due to reduced consciousness, or other causes of reduced verbal response and were excluded from this analysis; many of whom met DSM-5 criteria for delirium. Secondary analysis suggests that selected cognitive and observational items from the CAM and IDEA cognitive screen may be as effective as the full screening tools in identifying delirium even in unresponsive patients. CONCLUSION: Both instruments appeared useful for delirium screening in this inpatient setting, but had significant limitations. The combination of assessment items identified may form the basis of a brief, simple delirium screening tool suitable for use by non-specialist clinicians. Further development work is needed.

A North American perspective of content and quality of websites in the English language on childhood-onset lupus erythematosus.

Objective The objective of this article is to examine the quality, content, and readability of information and resources in the English language and accessible on the internet by pediatric patients with systemic lupus erythematosus (SLE) and their families in North America. Methods Keywords relevant to SLE were generated by an undergraduate student, a first-year medical student, and a third-year pediatric resident, and a search was conducted across five commonly used search engines. Quality of information found was evaluated independently by an undergraduate student, a graduate student, a first-year medical student, and a third-year pediatric resident using the DISCERN tool. Two pediatric rheumatologists assessed website accuracy and completeness. Readability of websites was determined using the Flesch-Kincaid grade level and Reading Ease score. Results Out of 2000 websites generated in the search, only 34 unique websites met inclusion criteria. Only 16 of these websites had DISCERN scores above 50% (fair quality). Overall quality of website information was fair with mean ±standard deviation (SD) DISCERN quality score of 44 ± 7 (range: 30-56). Only nine websites of 34 had DISCERN scores above 50 (>66%, indicating greater quality) and were further assessed for completeness. Flesch-Kincaid grade level was 11 ± 1 (mean±SD) and reading ease score was 39 ± 10 (mean±SD, range of 11-61). Conclusion Our study highlights the need for more complete, readable information regarding the unique needs of pediatric patients with childhood-onset SLE and their families.

Young Children's ability to Discriminate between Antisocial and Prosocial Teases.

The present study was designed to (a) examine 5- to 8-year-old children's ability to discriminate between antisocial and prosocial teases and (b) determine whether their age and experiences within the home are associated with their ability to recognize these two types of teases. Results revealed that the 5- to 8-year-old children were able to discriminate between antisocial and prosocial teases. Although the children's parents or legal guardians indicated that the children had more frequent experience with prosocial than antisocial teases in the home, (a) the children were better able to correctly identify the intent of antisocial teasers than prosocial teasers and (b) the parents or legal guardians (correctly) indicated that their child would be better able to recognize an antisocial tease than a prosocial tease. Despite the finding that the children's comprehension of antisocial teasing tended to exceed their comprehension of prosocial teasing, the findings indicate that being relatively young (i.e., 5-6 years old vs. 7-8 years old) and having relatively frequent experience with antisocial teasing in the home may be associated with some children's difficulty in recognizing the intent behind antisocial teases.

Consumption of Nuts and Seeds and Telomere Length in 5,582 Men and Women of the National Health and Nutrition Examination Survey (NHANES).

OBJECTIVES: Consumption of nuts and seeds is associated favorably with all-cause mortality. Nuts and seeds could reduce disease and prolong life by influencing telomeres. Telomere length is a good indicator of the senescence of cells. The purpose of the present study was to determine the relationship between nuts and seeds intake and leukocyte telomere length, a biomarker of biologic aging. DESIGN: Cross-sectional. SETTING AND PARTICIPANTS: A total of 5,582 randomly selected men and women from the National Health and Nutrition Examination Survey (NHANES), 1999-2002, were studied. MEASUREMENTS: DNA was obtained via blood samples. Telomere length was assessed using the quantitative polymerase chain reaction method. A validated, multi-pass, 24-h recall dietary assessment, administered by NHANES, was employed to quantify consumption of nuts and seeds. RESULTS: Nuts and seeds intake was positively and linearly associated with telomere length. For each 1-percent of total energy derived from nuts and seeds, telomere length was 5 base pairs longer (F=8.6, P=0.0065). Given the age-related rate of telomere shortening was 15.4 base pairs per year (F=581.1, P<0.0001), adults of the same age had more than 1.5 years of reduced cell aging if they consumed 5% of their total energy from nuts and seeds. CONCLUSIONS: Consumption of nuts and seeds accounts for meaningful decreases in biologic aging and cell senescence. The findings reinforce the recommendations of the 2015-2020 Dietary Guidelines for Americans, which encourage the consumption of nuts and seeds as part of a healthy diet.