Identification of CNTN2 as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing in Drosophila.

Loss of function mutations in the X-linked PIGA gene lead to PIGA-CDG, an ultra-rare congenital disorder of glycosylation (CDG), typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGA S132C , an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great-uncle also carry PIGA S132C , but neither presents with symptoms associated with PIGA-CDG. We hypothesized genetic modifiers may contribute to this reduced penetrance. Using whole genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in carriers and possible protective variants found in the carriers and not in the probands. Candidate variants included heterozygous, damaging variants in three genes also involved directly in GPI-anchor biosynthesis and a few genes involved in other glycosylation pathways or encoding GPI-anchored proteins. We functionally tested the predicted modifiers using a Drosophila eye-based model of PIGA-CDG. We found that loss of CNTN2 , a predicted protective modifier, rescues loss of PIGA in Drosophila eye-based model, like what we predict in the family. Further testing found that loss of CNTN2 also rescues patient-relevant phenotypes, including seizures and climbing defects in Drosophila neurological models of PIGA-CDG. By using pedigree information, genome sequencing, and in vivo testing, we identified CNTN2 as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in human pedigrees may lead to pathways and targets that may be developed into therapies.

Effects of exercise on sleep in patients with epilepsy: A systematic review.

Exercise interventions in epilepsy have been shown to improve seizure frequency, physical capacity, quality of life, mood, and cognitive functioning. However, the effectiveness of exercise in improving sleep in epilepsy is less clear. The purpose of this report is to identify the published literature regarding exercise interventions in people with epilepsy to determine 1) what proportion of published clinical trials assess sleep as an outcome, and 2) what benefits of exercise interventions on sleep have been observed. We searched the PubMed, PsycINFO, and SCOPUS electronic databases using the search terms "epilepsy AND [exercise OR physical activity]" and identified 23 articles reporting on 18 unique clinical trials. Nine studies were conducted in adults, five in children, and four in adults and children with active seizures, controlled seizures, or both. Exercise modalities included aerobic exercise, strength training, walking, and yoga, among others, and some also included educational and motivational components. Exercise effects on sleep were tested in four studies, two of which only included indirect measures of sleep- and rest-related fatigue, with mixed results. Of the two reports assessing sleep directly, one reported marginal non-significant improvements in subjective sleep quality and no improvements in objective sleep quality in children after twelve weeks of walking, and the other reported no benefits in subjective sleep quality after twelve weeks of combined aerobic, strength, and flexibility training in adults. Given the health benefits of sleep and detrimental effects of sleep deprivation in epilepsy, epilepsy researchers need to assess the effects of exercise interventions on sleep.

Effectiveness of specialised support surface modes in preventing pressure injuries in intensive care: A systematic review and meta-analysis.

BACKGROUND: Patients in intensive care units (ICU) are at an increased risk of pressure injuries. In ICUs, specialised support surfaces are an intervention often used to prevent pressure injuries. This systematic review and meta-analysis aimed to ascertain the effectiveness of different specialised support surface modes for preventing pressure injuries to adult ICU patients. METHODS: Ovid MEDLINE, Ovid Embase, EBSCO CINAHL, PEDro, Cochrane Library, Clinicaltrials.gov and eligible paper references were searched for appropriate studies. Studies were included if they investigated both dynamic support surface modes low-air-loss (LAL) and alternating pressure (AP), involved adult ICU patients (≥18 years old), and investigated pressure injury incidence. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Mixed Methods Appraisal Tool (MMAT) checklists were used for reporting and quality assessment. Risk ratios (RRs) with 95 % Confidence Intervals (CIs) were used to summarise pressure injury incidence. The pooled RR was calculated with the random-effects model using the Mantel-Haenszel method. Further secondary analysis examined length of stay (LoS) and severity of illness. RESULTS: The four included studies involved 3,308 patients. These studies were heterogeneous in design. When AP surface mode was compared with LAL surface mode, there was no significant difference in the occurrence of pressure injury (8.9 % versus 10.9 %, RR 0.64). Mattress mode also had no direct association with length of stay and severity of illness. CONCLUSION: This systematic review and meta-analysis found no significant difference in the effectiveness of LAL and AP support surface modes in preventing pressure injuries in adult ICU patients. IMPLICATIONS FOR CLINICAL PRACTICE: Clinicians should remember that mattresses are just one element within strategies to prevent pressure injuries in ICUs. The equivocal findings of this systematic review highlight the complexity of preventing pressure injuries and underscore the importance of holistic nursing care.

Infants Infer Social Relationships Between Individuals Who Engage in Imitative Social Interactions.

Infants are born into rich social networks and are faced with the challenge of learning about them. When infants observe social interactions, they make predictions about future behavior, but it is not clear whether these predictions are based on social dispositions, social relationships, or both. The current studies (N = 188, N = 90 males) address this question in 12-month-old infants and 16- to 18-month-old toddlers who observe social interactions involving imitation. In Studies 1 and 3, infants and toddlers expected that imitators, compared to non-imitators, would respond to their social partners' distress. Likewise, they expected the targets of imitation, compared to non-targets, to respond to their partner's distress. In Study 2, these expectations did not generalize to interactions with a new partner, providing evidence that infants learned about the relationships between individuals as opposed to their dispositions. In Study 3, infants did not make predictions about responses to laughter, suggesting that infants see imitation as indicative of a specific kind of social relationship. Together, these results provide evidence that imitative interactions support infants' and toddlers' learning about the social relationships connecting unknown individuals.

Anti-spike antibody durability after SARS-CoV-2 vaccination in adolescent solid organ transplant recipients.

BACKGROUND: Adolescent solid organ transplant recipients (aSOTRs) who received three doses of the COVID-19 mRNA vaccine experience high seroconversion rates and antibody persistence for up to 3 months. Long-term antibody durability beyond this timeframe following three doses of the SARS-CoV-2 mRNA vaccine remains unknown. We describe antibody responses 6 months following the third vaccine dose (D3) of the BNT162b2 mRNA vaccination among aSOTRs. METHODS: Participants in a multi-center, observational cohort who received the third dose of the vaccine were analyzed for antibodies to the SARS-CoV-2 spike protein receptor-binding domain (Roche Elecsys anti-SARS-CoV-2-S positive: ≥0.8, maximum: >2500 U/mL). Samples were collected at 1-, 3-, and 6-months post-D3. Participants were surveyed at each timepoint and at 12-months post-D3. RESULTS: All 34 participants had positive anti-RBD antibody titers 6 months post-D3. Variations in titers occurred between 3 and 6 months post-D3, with 8/28 (29%) having decreased antibody levels at 6 months compared to 3 months and 2/28 (7%) reporting increased titers at 6 months. The remaining 18/28 (64%) had unchanged antibody titers compared to 3-month post-D3 levels. A total of 4/34 (12%) reported breakthrough infection within 6 months and 3/32 (9%) reported infection after 6-12 months following the third dose of the SARS-CoV-2 mRNA vaccine. CONCLUSIONS: The results suggest that antibody durability persists up to 6 months following three doses of the SARS-CoV-2 mRNA in aSOTRs. Demography and transplant characteristics did not differ for those who experienced antibody weaning. Breakthrough infections did occur, reflecting immune-evasive nature of novel variants such as Omicron.

Parent Perceptions and Opinions of Universal Free School Meals in Arizona.

To support families during the COVID-19 pandemic, the USDA allowed all US schools to offer meals at no cost regardless of family income, a policy referred to as Universal Free Meals or Healthy School Meals for All (HSM4A). Despite the recognized benefits and popularity of HSM4A during the pandemic, the policy expired in June 2022. The goal of this study was to gather perceptions of parents in Arizona about school meals, the HSM4A program, and the discontinuation of HSM4A. In collaboration with a local anti-hunger group, using an online survey distributed in September and October 2022, we collected data from a diverse sample of over 2000 parents living in Arizona. Parents unequivocally supported HSM4A during the pandemic (97%) and expressed support for continuing to offer HSM4A (95%). High levels of support were seen across all groups in the study, including from individuals who identified as politically conservative. We also analyzed 750 responses to an open-ended question asking respondents to share their thoughts about offering meals to all Arizona students regardless of family income. The majority of emergent themes related to perceived benefits of HSM4A, including reducing financial burden and stress for families. Our findings will be useful for advocates and policy makers considering HSM4A legislation.

Omicron Infections in Vaccinated Pediatric Solid Organ Transplant Recipients.

SARS-CoV-2 infection during the Omicron period was frequent amongst a cohort of vaccinated pediatric solid organ transplant recipients (pSOTRs) despite robust anti-receptor-binding domain (anti-RBD) antibody response, suggesting poor neutralizing capacity against Omicron subvariants. Breakthrough infections among pSOTRs were overall limited in severity.

Impact of changes to invite methodology on equality of access to the National Breast Screening Programme in the South of England.

In response to the COVID-19 pandemic, a temporary change in policy was implemented in 2020. Breast screening services in England were advised to change from timed appointments to an open invitation for invitees to contact the service and arrange an appointment. This change to invitation methodology had potential benefits and risks including impacting inequalities in uptake. Qualitative data were collected by online questionnaire from 23 service providers and routinely collected quantitative uptake data were analysed to investigate the impact of open invitations on the National Programme in the South of England. Office for National Statistics and general practitioner (GP) practice profile data enabled the modelling of sociodemographic characteristics of breast screening invitees at each GP practice. Most services changed to open invitations (17/23), 82% of which altered administrative capacity and/or procedures to accommodate this change. Logistic benefits were reported including a more consistent flow of participants, fewer long gaps and fewer wasted slots. The change to open invitations was associated with a 7.2% reduction in the percentage of participants screened, accounting for participant sociodemographics and historical screening provider uptake. The inequality in screening uptake experienced by participants of minority ethnic background was exacerbated by the change to open invitations. Open invitations, whilst affording logistic benefits in an unprecedented pandemic era, were associated with reduced overall uptake and exacerbation of existing health inequality experienced by women of minority ethnic background. The broader impact on services highlighted the need for sustainability of measures taken to accommodate such operational changes.

Effect of Dental Varnishes in Prevention of Enamel Demineralization Adjacent to Orthodontic Brackets.

Aim: The aim of the current research was to assess the ability of different dental varnishes in averting enamel demineralization adjoining the orthodontic brackets. Materials and Methods: Seventy-five premolars devoid of dental caries that were subjected to extraction for orthodontic purposes were employed in this research. The surface of enamel was etched with 37% phosphoric acid and subjected to primer application. Individual brackets were placed on the midregion of the buccal surfaces of the premolars with Transbond™ XT adhesive. Postbracket bonding, the dry premolar tooth samples were set aside cautiously. The samples were then allocated to three groups: Group I: Duraphat Varnish, Group II: Clinpro XT Varnish, and Group III: Profluorid Varnish. Every sample was independently subjected to immersion in demineralizing solution for a period of 96 h at 37°C in an incubator. Areas of demineralization were evaluated by documenting the microhardness along the severed surface using a microhardness tester equipped with a Vickers diamond. Results: The highest surface microhardness was noted with Profluorid Varnish group at 328.48 ± 1.12 in pursuit by Clinpro XT Varnish group at 322.08 ± 0.04 as well as Duraphat Varnish group at 307.42 ± 0.28 with a statistically noteworthy dissimilarity amid the groups. Conclusion: In conclusion, the three varnishes employed had an influence on the prevention of enamel demineralization surrounding the orthodontic brackets. Profluorid varnish however exhibited maximum efficiency in avoiding enamel demineralization versus Clinpro XT varnish as well as Duraphat varnish group.

Glucagon-like peptide-1 receptor agonists use for type 2 diabetes mellitus in end-stage renal disease.

BACKGROUND: Management of type 2 diabetes mellitus (T2DM) in patients with end-stage renal disease (ESRD) remains a challenge given limited data. Although current guidelines recommend use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of T2DM in patients with concomitant chronic kidney disease, supporting safety and efficacy evidence is lacking for patients with ESRD or hemodialysis. OBJECTIVE: This retrospective study was conducted to evaluate the efficacy and safety of GLP-1 RAs for the treatment of T2DM in patients with ESRD. DESIGN, SETTING, AND PARTICIPANTS: This is a single-centered, multifacility retrospective cohort analysis. Patients were included if they had a diagnosis of T2DM and ESRD and were prescribed a GLP-1 RA. Patients were excluded if the GLP-1 RA was prescribed solely for weight loss. OUTCOME MEASURES: The primary outcome was change in A1C. Secondary outcomes included (1) incidence of acute kidney injury (AKI), (2) change in weight, (3) change in estimated glomerular filtration rate, (4) ability to discontinue basal or bolus insulin, and (5) incidence of emergent hypoglycemia. RESULTS: There were 46 unique patients and 64 individual GLP-1 RA prescriptions included. The mean reduction in A1C was 0.8%. There were 10 incidences of AKI, although none occurred in the semaglutide cohort. Emergent hypoglycemia occurred in 3 patients who were all prescribed concomitant insulin. CONCLUSION: Results from this retrospective review provide additional real-world data on use of GLP-1 RAs in this unique population. Prospective studies to control for confounding factors are warranted given that GLP-1RAs are a safer alternative to insulin in this high-risk population.

Determination of Labiopalatal Angulation of Maxillary Anterior Teeth Using Manual Method and Digital Methods: A Comparative Study.

AIM: The aim of the present study was to evaluate labiopalatal angulation of maxillary anterior teeth using Custom-made jig, Profile projector, and ImageJ computer software methods. MATERIALS AND METHODS: The subjects for this study were selected in the age-group of 20-30 years having permanent dentition, including 2nd molars and bilateral Angle's class 1 molar and canine relationship. Recording the labiopalatal angulation in proximal view was carried out by using one manual method and two digital methods namely using Custom-made jig, Profile projector, and ImageJ computer software, respectively. Alginate impressions were made for the subjects, and the spatial relationship of the maxilla to the cranium was recorded using a facebow. The casts were mounted in a semi-adjustable articulator, and the articulated mounted casts with the mounting ring were transferred to the Custom-made jig, and angulations were measured in proximal view. Digital methods of measurement were recorded by using Profile projector and ImageJ computer software methods. Data were tabulated and statistically analyzed. RESULTS: In males, the mean labiopalatal angulation of maxillary right and left maxillary canines of Custom-made jig was 91.94 ± 1.47 and 91.70 ± 1.68, in Profile projector method 87.41 ± 3.75 and 87.58 ± 3.79, and in ImageJ computer software 84.23 ± 5.72 and 83.29 ± 6.74, respectively. In females, Custom-made jig was 91.82 ± 1.55 and 92.17 ± 1.84, in Profile projector method 86.70 ± 5.58 and 86.94 ± 5.57, and in ImageJ computer software 82.76 ± 6.34 and 83.05 ± 6.12, respectively. There was a very high statistically significant difference found between different methods. CONCLUSION: In conclusion, the values obtained in the digital methods (i.e., both the Profile projector and ImageJ computer software) were more accurate than the manual method. However, the ImageJ computer software was most reliable in comparison with the values obtained in Profile projector. CLINICAL SIGNIFICANCE: The labiopalatal angulation of anterior teeth will act as a guideline in re-establishing the correct angulations and the anatomic contours of the maxillary arch to achieve the desired esthetics that provide adequate lip support and to restore the required functions.

Cannabidiol Add-On in Glycosylphosphatidylinositol-Related Drug-Resistant Epilepsy.

Background: Glycosylphosphatidylinositol-anchored protein deficiencies (GPI-ADs) are commonly associated with drug-resistant epilepsy (DRE). Cannabidiol (CBD) is approved for the adjunctive treatment of seizures in Dravet/Lennox-Gastaut Syndromes and Tuberous Sclerosis Complex. We report on the efficacy and safety of CBD for the treatment of DRE in patients with genetically proven GPI-AD. Patients and Methods: Patients received add-on treatment with purified GW-pharma CBD (Epidyolex®). Efficacy endpoints were the percentage of patients with ≥50% (responders) or >25<50% (partial responders) reduction in monthly seizures from baseline and at 12 (M12) months of follow-up. Safety was evaluated through adverse events (AEs) monitoring. Results: Six patients (5 males) were enrolled. The median age at seizures onset was 5 months and the syndromic diagnosis was early infantile developmental and epileptic encephalopathy in 4 patients and focal non-lesional epilepsy or GEFS+ in one patient each. Five out of six (83%) patients were responders at M12, while one was a partial responder. No severe AEs were reported. Mean prescribed CBD dose was 17.85 mg/kg/day and median treatment duration is currently 27 months. Conclusions: In summary, off-label treatment with CBD was effective and safe in patients with DRE due to GPI-ADs.

Muscarinic and NMDA Receptors in the Substantia Nigra Play a Role in Reward-Related Learning.

BACKGROUND: Reward-related learning, where animals form associations between rewards and stimuli (i.e., conditioned stimuli [CS]) that predict or accompany those rewards, is an essential adaptive function for survival. METHODS: In this study, we investigated the mechanisms underlying the acquisition and performance of conditioned approach learning with a focus on the role of muscarinic acetylcholine (mACh) and NMDA glutamate receptors in the substantia nigra (SN), a brain region implicated in reward and motor processes. RESULTS: Using RNAscope in situ hybridization assays, we found that dopamine neurons of the SN express muscarinic (mACh5), NMDA2a, NMDA2b, and NMDA2d receptor mRNA but not mACh4. NMDA, but not mACh5, receptor mRNA was also found on SN GABA neurons. In a conditioned approach paradigm, rats were exposed to 3 or 7 conditioning sessions during which light/tone (CS) presentations were paired with delivery of food pellets, followed by a test session with CS-only presentations. Intra-SN microinjections of scopolamine (a mACh receptor antagonist) or AP-5 (a NMDA receptor antagonist) were made either prior to each conditioning session (to test their effects on acquisition) or prior to the CS-only test (to test their effects on expression of the learned response). Scopolamine and AP-5 produced dose-dependent significant reductions in the acquisition, but not performance, of conditioned approach. CONCLUSIONS: These results suggest that SN mACh and NMDA receptors are key players in the acquisition, but not the expression, of reward-related learning. Importantly, these findings redefine the role of the SN, which has traditionally been known for its involvement in motor processes, and suggest that the SN possesses attributes consistent with a function as a hub of integration of primary reward and CS signals.

Non-instrumental actions can communicate roles and relationships, not just rituals.

Actions that do not have instrumental goals can communicate social goals that are not rituals. Many non-instrumental actions such as bowing or kissing communicate a commitment to or roles in dyadic relationships. What is unclear is when people understand such actions in terms of ritual and when they understand them in terms of relationships.

Intuitive Sociology: Children Recognize Decision-Making Structures and Prefer Groups With Less-Concentrated Power.

From an early age, children recognize that people belong to social groups. However, not all groups are structured in the same way. The current study asked whether children recognize and distinguish among different decision-making structures. If so, do they prefer some decision-making structures over others? In these studies, children were told stories about two groups that went camping. In the hierarchical group, one character made all the decisions; in the egalitarian group, each group member made one decision. Without being given explicit information about the group's structures, 6- to 8-year-old children, but not 4- and 5-year-old children, recognized that the two groups had different decision-making structures and preferred to interact with the group where decision-making was shared. Children also inferred that a new member of the egalitarian group would be more generous than a new member of the hierarchical group. Thus, from an early age, children's social reasoning includes the ability to compare social structures, which may be foundational for later complex political and moral reasoning.

Impact of a pharmacist-led outpatient telemedicine clinic on chronic obstructive pulmonary disease in a veteran population.

OBJECTIVES: The primary objective was to evaluate chronic obstructive pulmonary disease (COPD) interventions in a pharmacist-led telemedicine clinic. Secondary objectives were to quantify emergency department (ED) visits and hospitalizations for COPD exacerbations. SETTING: A single-center, outpatient telemedicine clinic within the Veterans Affairs (VA) Tennessee Valley Healthcare System from January 2021 to June 2021. PRACTICE DESCRIPTION: Patients with an active COPD diagnosis and assigned to a primary care team within the local VA were reviewed for enrollment. Visits were conducted through VA video connect or telephone. During these appointments, pertinent information was collected and pharmacotherapy and nonpharmacotherapy interventions were implemented to optimize COPD management. PRACTICE INNOVATION: Visits were conducted by a postgraduate year 2 ambulatory care pharmacy resident under supervision of a clinical pharmacy specialist with a scope of practice. Appointments were virtual to reduce coronavirus disease 2019 exposure and increase access to care. Patients were identified through a COPD patient report and provider referral to target high-risk patients. EVALUATION: Interventions made were documented at each visit. Chart review and patient interview were used to quantify ED visits or hospitalizations for COPD exacerbations occurring the year before or during clinic enrollment. RESULTS: Of 82 charts reviewed, 18 patients were eligible for enrollment. Eleven were followed as 7 patients did not show for initial visits. A total of 31 COPD interventions occurred including 13 nonpharmacotherapy (i.e., inhaler education, smoking cessation) and 18 pharmacotherapy (i.e., optimization of COPD regimens). An average of 3 COPD interventions were completed per patient followed. No ED visits and 2 hospitalizations for a COPD exacerbation occurred during the study period. This cohort had 1 ED visit and 10 hospitalizations the year before enrollment. CONCLUSION: This telemedicine clinic experience, albeit a small study population, suggests an opportunity for pharmacists to provide pharmacotherapy and nonpharmacotherapy interventions, which may improve COPD-related outcomes and access to care.

Infants infer potential social partners by observing the interactions of their parent with unknown others.

Infants are born into networks of individuals who are socially connected. How do infants begin learning which individuals are their own potential social partners? Using digitally edited videos, we showed 12-mo-old infants' social interactions between unknown individuals and their own parents. In studies 1 to 4, after their parent showed affiliation toward one puppet, infants expected that puppet to engage with them. In study 5, infants made the reverse inference; after a puppet engaged with them, the infants expected that puppet to respond to their parent. In each study, infants' inferences were specific to social interactions that involved their own parent as opposed to another infant's parent. Thus, infants combine observation of social interactions with knowledge of their preexisting relationship with their parent to discover which newly encountered individuals are potential social partners for themselves and their families.

Advantages and limitations of representing groups in terms of recursive utilities.

Group representations based on recursive utilities can be used to derive the same predictions as Pietraszewski in conflict situations. Additionally, these representations generalize to non-conflict situations, asymmetric relationships, and represent the stakes in a conflict. However, both proposals fail to represent asymmetries of power and responsibility and to account for generalizations from specific observed individuals to collections of non-observed individuals.

Preoperative risk assessment tools for morbidity after cardiac surgery: a systematic review.

BACKGROUND: Postoperative morbidity places considerable burden on health and resources. Thus, strategies to identify, predict, and reduce postoperative morbidity are needed. AIMS: To identify and explore existing preoperative risk assessment tools for morbidity after cardiac surgery. METHODS: Electronic databases (including MEDLINE, CINAHL, and Embase) were searched to December 2020 for preoperative risk assessment models for morbidity after adult cardiac surgery. Models exploring one isolated postoperative morbidity and those in patients having heart transplantation or congenital surgery were excluded. Data extraction and quality assessments were undertaken by two authors. RESULTS: From 2251 identified papers, 22 models were found. The majority (54.5%) were developed in the USA or Canada, defined morbidity outcome within the in-hospital period (90.9%), and focused on major morbidity. Considerable variation in morbidity definition was identified, with morbidity incidence between 4.3% and 52%. The majority (45.5%) defined morbidity and mortality separately but combined them to develop one model, while seven studies (33.3%) constructed a morbidity-specific model. Models contained between 5 and 50 variables. Commonly included variables were age, emergency surgery, left ventricular dysfunction, and reoperation/previous cardiac surgery, although definition differences across studies were observed. All models demonstrated at least reasonable discriminatory power [area under the receiver operating curve (0.61-0.82)]. CONCLUSION: Despite the methodological heterogeneity across models, all demonstrated at least reasonable discriminatory power and could be implemented depending on local preferences. Future strategies to identify, predict, and reduce morbidity after cardiac surgery should consider the ageing population and those with minor and/or multiple complex morbidities.