Postmodification with Polycations Enhances Key Properties of Alginate-Based Multicomponent Microcapsules.

Postmodification of alginate-based microspheres with polyelectrolytes (PEs) is commonly used in the cell encapsulation field to control microsphere stability and permeability. However, little is known about how different applied PEs shape the microsphere morphology and properties, particularly in vivo. Here, we addressed this question using model multicomponent alginate-based microcapsules postmodified with PEs of different charge and structure. We found that the postmodification can enhance or impair the mechanical resistance and biocompatibility of microcapsules implanted into a mouse model, with polycations surprisingly providing the best results. Confocal Raman microscopy and confocal laser scanning microscopy (CLSM) analyses revealed stable interpolyelectrolyte complex layers within the parent microcapsule, hindering the access of higher molar weight PEs into the microcapsule core. All microcapsules showed negative surface zeta potential, indicating that the postmodification PEs get hidden within the microcapsule membrane, which agrees with CLSM data. Human whole blood assay revealed complex behavior of microcapsules regarding their inflammatory and coagulation potential. Importantly, most of the postmodification PEs, including polycations, were found to be benign toward the encapsulated model cells.

Influence of Clinical and Genetic Factors on Propofol Dose Requirements: A Genome-wide Association Study.

BACKGROUND: Propofol is a widely used intravenous hypnotic. Dosing is based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. METHODS: This study considered 1,000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy (GE Healthcare, Finland). Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study. Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. RESULTS: Body mass index, smoking status, alcohol use, remifentanil dose (ln[mg · kg-1 · min-1]), and average State Entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5 × 10-8). The most significant associations were for single-nucleotide polymorphisms rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene, FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding the Kir2.1 potassium channel showed suggestive association (P = 4.7 × 10-7). None of these single-nucleotide polymorphisms are coding variants but possibly affect the regulation of nearby genes. None of the single-nucleotide polymorphisms previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in the data. CONCLUSIONS: In this first genome-wide association study exploring propofol requirements, This study discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN, and KCNJ2 in propofol anesthesia warrant further studies.

Storylines of family medicine VIII: clinical approaches.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'VIII: clinical approaches', authors address the following themes: 'Evaluation, diagnosis and management I-toward a working diagnosis', 'Evaluation, diagnosis and management II-process steps', 'Interweaving integrative medicine and family medicine', 'Halfway-the art of clinical judgment', 'Seamless integration in family medicine-team-based care', 'Technology-uncovering stories from noise' and 'Caring for patients with multiple long-term conditions'. May readers recognise in these essays the uniqueness of a family medicine approach to care.

Associations of menopausal status and eating behaviour with subjective measures of sleep.

Eating and sleeping behaviour are known to interact with each other, yet research is limited in the context of menopausal women. The aim of this study was to examine whether menopausal status is associated with perceived problems in sleeping. Furthermore, we studied different aspects of eating behaviour as potential risk factors for poor sleep in menopausal women. The present study is exploratory in nature, thus the results should be interpreted as hypothesis-generating. We analysed the sleeping and eating behaviour of 1098 women aged 47-55 years and represented different menopausal statuses with regression analyses. Over 20% of them reported fairly poor or poor perceived sleep quality. A higher number of postmenopausal women reported experiencing at least fairly poor sleep quality compared with the other menopausal groups. However, in regression models controlled for several confounding factors menopausal status was not associated with measures of sleep. Women who reported more snacking-type eating behaviour were more likely to report shorter sleep duration, and more daytime tiredness. Externally cued eating was associated with shorter sleep duration and emotional eating was associated with experiencing daytime tiredness. However, after adjusting for multiple testing, it appears that eating behaviour is associated only with daytime tiredness. Menopausal women with sleeping problems may benefit from nutritional interventions targeting eating behaviour.

Where Do Adults in the United States Obtain Cannabis? A Nationally Representative Study Examining the Relationships Between Sociodemographic Factors, Cannabis Use Characteristics and Sources of Cannabis.

OBJECTIVE: Characterization of population subgroups based on where they acquire cannabis is unexplored. We examine relationships between sociodemographic characteristics, cannabis use modality, risky cannabis use, and source of cannabis. METHOD: Analyzing a representative sample (unweighted n = 8,089) of U.S. adults living in medical cannabis-permitting states with past-year cannabis use from the 2021 National Survey on Drug Use and Health, we determined source of last cannabis used. Outcome groups were purchased from a dispensary, purchased from another source, or nonpurchased source. Incorporating the complex survey design, descriptive statistics and adjusted multinomial logistic regressions evaluated associations between sociodemographic, individual cannabis use characteristics, and source of cannabis. Secondary analyses described cannabis purchasing characteristics among the subsample who last purchased cannabis. RESULTS: Purchasing from a dispensary was the most common source of cannabis (42.5%). Significant relationships between sociodemographic characteristics, cannabis use modality, risky cannabis use, and source of cannabis were found. Recent cannabis initiates and those with cannabis vaporizer use had an increased likelihood of purchasing cannabis from a dispensary. Purchasing from a nondispensary source was most likely among those with daily cannabis use, past-month blunt use, past-year driving under the influence, cannabis use disorder, and cannabis and alcohol co-use. Among those purchasing cannabis, joints and other forms of cannabis were more likely to be purchased from a dispensary than purchased from other sources. CONCLUSIONS: We identified key sociodemographic and cannabis use characteristics that may influence where individuals obtain cannabis, which are important for cannabis behavior surveillance and cannabis use prevention and intervention strategies to consider.

Acute neuroinflammation leads to disruption of neuronal chloride regulation and consequent hyperexcitability in the dentate gyrus.

Neuroinflammation is a salient part of diverse neurological and psychiatric pathologies that associate with neuronal hyperexcitability, but the underlying molecular and cellular mechanisms remain to be identified. Here, we show that peripheral injection of lipopolysaccharide (LPS) renders the dentate gyrus (DG) hyperexcitable to perforant pathway stimulation in vivo and increases the internal spiking propensity of dentate granule cells (DGCs) in vitro 24 h post-injection (hpi). In parallel, LPS leads to a prominent downregulation of chloride extrusion via KCC2 and to the emergence of NKCC1-mediated chloride uptake in DGCs under experimental conditions optimized to detect specific changes in transporter efficacy. These data show that acute neuroinflammation leads to disruption of neuronal chloride regulation, which unequivocally results in a loss of GABAergic inhibition in the DGCs, collapsing the gating function of the DG. The present work provides a mechanistic explanation for neuroinflammation-driven hyperexcitability and consequent cognitive disturbance.

Early is Better: Report of a Cowden Syndrome.

In the clinical practice, it is not common for pediatricians to visit children with overgrowth phenotype. When it happens, it is important to focus on the age of manifestations and research the pathogenic causes using appropriate genetic test. Cowden syndrome is one of these rare causes; it is an autosomal dominant genodermatosis characterized by multiple hamartomas of ectodermal, mesodermal, and endodermal origin. It is caused by loss of function mutations in the phosphatase and tensin homolog (PTEN) gene located on chromosome 10q23.1 Loss of function of the PTEN gene contributes to overgrowth and risk for a variety of cancers including breast, thyroid, endometrium, skin, kidneys, and colon. The early diagnosis of Cowden disease allows a careful monitoring of the patients who are facing the risk of cancer transformation, which is the principal complication of the condition.

Torque changes of anchorage units in preadolescent patients treated with a digitally designed tooth-borne expander anchored to deciduous vs. permanent molars.

AIM: To compare the effects on permanent or deciduous anchorage dental units in patients treated with a digitally designed palatal expander. METHODS: Inclusion criteria were the following: presence of maxillary transverse deficiency, no previous orthodontic treatment, no extractions, absence of agenesis, congenital pathologies and cranio-maxillofacial malformations. Twenty patients (11 males, 9 females, 11 ± 1.8 years) received a digitally designed and metal printed palatal expander anchored on first permanent molars and 1 activation per day for 30 days (Group 1). Twenty-one patients (12 males, 9 females, 8.6 ± 1.4 years) received a digitally designed and metal printed palatal expander anchored on second deciduous molars and 2 activations per day for 14 days (Group 2). Digital intraoral scans were taken before expansion and after device removal, and torque and the palatal transverse diameter were digitally measured. The FDI notation was used to indicate each tooth CONCLUSION: Less dental torque augmentation was produced in Group 2. RESULTS: Significant intragroup differences over time were found in Group 1 considering the torque of teeth 1.6, 1.4, 1.3, 2.1, 2.4, 2.5, 2.6. Significant differences between groups were found regarding the longitudinal change in torque of teeth 1.5, 2.4 and 2.5. Significant intragroup differences over time were found in both groups considering all transverse diameter parameters. No significant differences were found between groups in the transverse diameter modifications over time. CONCLUSION: Less dental torque augmentation was produced in Group 2.

Food-related consumer behaviours in times of crisis: Changes in the wake of the Ukraine war, rising prices and the aftermath of the COVID-19 pandemic.

When the COVID-19 pandemic subsided, the war in Ukraine led to further disruptions in consumers' daily behaviours, with rising prices for food and energy. We conducted a survey study on self-reported changes in food-related consumer behaviour in ten European countries and compared the results to a similar study conducted two years ago. A latent class cluster analysis distinguished five clusters and showed that different types of consumers can be distinguished based on how they react to the crisis as regards their eating habits. 19% of survey participants reported no major changes, and 32% reported changes mostly in terms of more price sensitivity. Among those that reported changes beyond reacting to higher prices, there are indications of more mindful eating and more deliberate choices. The changes already found earlier in response to the COVID-19 pandemic therefore seem to have been strengthened and supplemented by reactions to price increases. The results present a challenge to the food industry in terms of supplying healthy and sustainable food at affordable prices.

Hyperemesis gravidarum: Associations with personal and family history of nausea.

INTRODUCTION: The pathogenesis and risk factors for hyperemesis gravidarum, excessive nausea and vomiting of pregnancy, are not adequately recognized. In our previous study, we found that women with a personal history of nausea in different situations and a family history of nausea and vomiting of pregnancy (NVP) were more likely to have severe NVP. The present study focuses on these themes in association with hyperemesis gravidarum in a hospital setting. MATERIAL AND METHODS: Women with hyperemesis gravidarum (n = 102) were recruited from among patients hospitalized due to hyperemesis gravidarum in Turku University Hospital, Finland. Our control group (Non-NVP group, n = 138) consisted of pregnant women with no NVP. Personal history of nausea in different situations was inquired about in relation to "motion sickness", "seasickness", "migraine", "other kind of headache", "after anesthesia", "during the use of contraception", and "other kinds of nausea". Relatives with NVP were divided into first-degree (mother and sisters) and second-degree (more distant) relatives. RESULTS: In univariate analysis, a personal history of motion sickness, seasickness, nausea related to migraine, nausea with other headache and nausea in other situations were associated with hyperemesis gravidarum. After adjusting for age, parity, pre-pregnancy body mass index, marital status, and smoking, motion sickness (adjusted odds ratio [aOR] 5.24, 95% confidence interval [CI] 2.67-10.31, p < 0.0001), seasickness (aOR 4.82, 95% CI 2.32-10.03, p < 0.0001), nausea related to migraine (aOR 3.00, 95% CI 1.58-5.70, p < 0.001), and nausea in other situations (aOR 2.65, 95% CI 1.13-6.20, p = 0.025) remained significant. In multivariable analysis with all history of nausea variables, motion sickness (OR 2.76, 95% CI 1.29-5.89, p = 0.009) and nausea related to migraine (OR 3.10, 95% CI 1.40-6.86, p = 0.005) were associated with hyperemesis gravidarum. Having any affected relative (OR 3.51, 95%CI 1.84-6.73, p = 0.0002), especially a first-degree relative (OR 3.06, 95% CI 1.62-5.79, p = 0.0006), was also associated with hyperemesis gravidarum. Adjustment did not change the results. CONCLUSIONS: Women with a personal history of nausea or a family history of NVP are more likely to suffer from hyperemesis gravidarum. These results are beneficial to better identify and help women at risk for hyperemesis gravidarum.

Clinical and genetic factors associated with post-operative nausea and vomiting after propofol anaesthesia.

BACKGROUND: The incidence of post-operative nausea and vomiting (PONV) remains at about 30% despite all therapeutic efforts to reduce it. The clinical risk factors guiding the prophylactic treatment are well established, but genetic factors associated with PONV remain poorly known. The aim of this study was to explore clinical and genetic factors impacting PONV by performing a genome-wide association study (GWAS) together with relevant clinical factors as covariates, and systematically attempt to replicate previously reported PONV associations. Relevant clinical factors are explored with logistic regression model. METHODS: This was an observational case control study in Helsinki University Hospital between 1 August 2006 and 31 December 2010. One thousand consenting women with elevated risk for PONV, undergoing breast cancer surgery with standardised propofol anaesthesia and antiemetics. After exclusions for clinical reasons and failed genotyping, 815 patients were included with 187 PONV cases and 628 controls. Emergence of PONV up to 7th post-operative day was recorded. PONV at 2-24 h after surgery was selected to be the primary outcome. The GWAS explored associations between PONV and 653 034 genetic variants. Replication attempts included 31 variants in 16 genes. RESULTS: The overall incidence of PONV up to 7th post-operative day was 35%, where 3% had PONV at 0-2 h and 23% at 2-24 h after surgery. Age, American Society of Anaesthesiologists status, the amount of oxycodone used in the post-anaesthesia care unit, smoking status, previous PONV, and history of motion sickness were statistically significant predictive factors in the logistic model. The receiver operating characteristic-area under the curve of 0.75 (95% CI 0.71-0.79) was calculated for the model. The GWAS identified six variants with suggestive association to PONV (p < 1 × 10-5 ). Of the previously reported variants, association with the DRD2 variant rs18004972 (TaqIA) was replicated (p = .028). CONCLUSIONS: Our GWAS approach did not identify any high-impact PONV susceptibility variants. The results provide some support for a role of dopamine D2 receptors in PONV.

FinnGen provides genetic insights from a well-phenotyped isolated population.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Early adulthood and current physical activity and their association with symptoms of pelvic floor disorders in middle-aged women: An observational study with retrospective physical activity assessment.

OBJECTIVE: To investigate associations of early and middle adulthood physical activity (PA) with symptoms of pelvic floor disorders (PFDs), i.e. stress urinary incontinence (SUI), urge urinary incontinence (UUI), faecal incontinence (FI), constipation or defecation difficulties (CDDs) and feeling of pelvic organ prolapse (POP) among middle-aged women. DESIGN: A cross-sectional, observational study with retrospective PA assessment. SETTING: University Research Laboratory. SAMPLE: A random population sample of 1098 Finnish women aged 47-55 years. METHODS: Early adulthood PA, current PA, and demographic and gynaecological variables were assessed using self-report questionnaires. Logistic regression analyses were applied to study associations of PA variables with symptoms of PFDs. Potential confounding effects of demographic and gynaecological variables were controlled in multiple logistic regression models. MAIN OUTCOME MEASURES: Structured questionnaire-assessed retrospective PA assessment at the age of 17-29 years, current PA at middle age, and prevalence of symptoms of CDD, FI, POP, SUI and UUI. RESULTS: Current PA was not independently associated with the occurrence of the symptoms of PFDs. Middle-aged women with an early adulthood history of competitive sports were more likely to experience symptoms of UUI (OR 2.16, 95% CI 1.10-4.24, p = 0.025) but not symptoms of SUI, FI, CDD or POP, whereas women with a history of regular PA were more likely to experience symptoms of FI (OR 4.41, 95% CI 1.05-18.49, p = 0.043) but no other symptoms of PFDs. CONCLUSIONS: Competitive sports during early adulthood may increase the risk of UUI in middle age. Regular PA during early adulthood may increase the risk of FI.

How Adolescents and Parents See Their Moral Responsibilities With Regard to Adolescents Using Alcohol-A Deductive Secondary Analysis.

BACKGROUND: This study described how adolescents and the parents saw their moral responsibilities with regard to adolescents using alcohol. METHODS: This was a deductive secondary analysis, based on Hart's taxonomy of moral responsibility. The primary studies were based on 19 group interviews with 87 adolescents aged 14-16 and 17 interviews with 20 parents. Voluntary participants were recruited by purposive sampling from two public schools in Finland. RESULTS: Role responsibilities comprised of adolescents taking care of themselves and parents providing authority figures and helping adolescents to make rational decisions about alcohol. Capacity responsibilities referred to adolescents' abilities to make independent decisions on using alcohol and their developing abilities to control their actions. Parents required abilities to get involved in and show an interest in their children's everyday lives. Causal responsibilities focused on ensuring that adolescents did not cause harm when they used alcohol, and parents had to acknowledge and react to the consequences. Liability responsibilities were about the law on alcohol use and responsibilities for any legal consequences. The role schools could play was important. CONCLUSIONS: Adolescents and parents had wide-ranging responsibilities related to the adolescents' using alcohol and school nurses could play an important role in healthy decisions.

Expression patterns of NKCC1 in neurons and non-neuronal cells during cortico-hippocampal development.

The Na-K-2Cl cotransporter NKCC1 is widely expressed in cells within and outside the brain. However, our understanding of its roles in brain functions throughout development, as well as in neuropsychiatric and neurological disorders, has been severely hindered by the lack of reliable data on its developmental and (sub)cellular expression patterns. We provide here the first properly controlled analysis of NKCC1 protein expression in various cell types of the mouse brain using custom-made antibodies and an NKCC1 knock-out validated immunohistochemical procedure, with parallel data based on advanced mRNA approaches. NKCC1 protein and mRNA are expressed at remarkably high levels in oligodendrocytes. In immature neurons, NKCC1 protein was located in the somata, whereas in adult neurons, only NKCC1 mRNA could be clearly detected. NKCC1 immunoreactivity is also seen in microglia, astrocytes, developing pericytes, and in progenitor cells of the dentate gyrus. Finally, a differential expression of NKCC1 splice variants was observed, with NKCC1a predominating in non-neuronal cells and NKCC1b in neurons. Taken together, our data provide a cellular basis for understanding NKCC1 functions in the brain and enable the identification of major limitations and promises in the development of neuron-targeting NKCC1-blockers.

Dandy-Walker malformation and variants: clinical features and associated anomalies in 28 affected children-a single retrospective study and a review of the literature.

OBJECTIVE: To investigate the clinical characteristics, the neuroimaging features and associated anomalies observed in children affected by Dandy-Walker malformations (DWM) and variants (DWV) in a single tertiary hospital in Catania and compare our data to their existent in the literature. METHODS: A retrospective case series using the medical records has been performed on 28 children diagnosed with DWM and DWV admitted to a single tertiary section of Pediatric Neurology, Department of Catania, Italy from January 2005 to January 2021. We reviewed the neuroimaging using the new diagnostic criteria of Klein et al. RESULTS: Associated anomalies were frequently reported. Among these, hydrocephalus was found in 13/28 (48%), and hydrocephalus plus corpus callosum anomalies in three children (10%). We described corpus callosum, cardiac and genitourinary anomalies in 2/28 (7%), 3/28 (10%), and 3/28 (10%), respectively. The most common clinical features were the developmental delay and epilepsy observed in 19/28 (67%) and in 9/28 (32%) of the cases. The first exam at the diagnosis was MRI in 17/28 patients, followed by transfontanellar ultrasound in 5/28, computed tomography in 4/28 and prenatal ultrasound in 2/28. To note, a child with DWM was affected by Down syndrome and one by congenital disorders of N-linked glycosylation (CDG-IId). CONCLUSIONS: Children with DWV were more commonly observed than children with DWM. Hydrocephalus is an anomaly, frequently and equally reported in both DWM and DMV. Perinatal complications were frequent adverse events with severe respiratory distress and need for cardiopulmonary resuscitation. Cognitive involvement and epilepsy were the most common comorbidities. Single DWV is associated with a better developmental outcome.