PURPOSE: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.

• MeSH
• Child MeSH
• Phenotype * MeSH
• Genetic Association Studies MeSH
• Heterozygote MeSH
• Infant MeSH
• Humans MeSH
• Mutation, Missense * genetics   MeSH
• Adolescent MeSH
• Neurodevelopmental Disorders * genetics   pathology   MeSH
• Child, Preschool MeSH
• Calcium Channels, T-Type * genetics   metabolism   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

• MeSH
• Alzheimer Disease * genetics   MeSH
• Genome-Wide Association Study methods   MeSH
• Genetic Predisposition to Disease genetics   MeSH
• X Chromosome Inactivation genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Humans MeSH
• Chromosomes, Human, X * genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. It has been suggested that neurodevelopmental factors contribute to the etiology of BD, but a specific neurodevelopmental phenotype (NDP) of the disorder has not been identified. Our objective was to define and characterize an NDP in BD and validate its associations with clinical outcomes, polygenic risk scores, and treatment responses. METHODS: We analyzed the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort of 4468 patients with BD, a validation cohort of 101 patients with BD, and 2 independent replication datasets of 274 and 89 patients with BD. Using factor analyses, we identified a set of criteria for defining NDP. Next, we developed a scoring system for NDP load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and gender with bootstrap replications. RESULTS: Our study established an NDP in BD consisting of 9 clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention-deficit/hyperactivity disorder, early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, and specific learning disorders. Patients with higher NDP load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between NDP load and polygenic risk score for attention-deficit/hyperactivity disorder, suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and attention-deficit/hyperactivity disorder. CONCLUSIONS: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

• MeSH
• Bipolar Disorder * genetics   MeSH
• Adult MeSH
• Phenotype * MeSH
• Attention Deficit Disorder with Hyperactivity genetics   MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Multifactorial Inheritance genetics   MeSH
• Neurodevelopmental Disorders genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. METHODS: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. RESULTS: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating - sum of boxes, clinical dementia rating - global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from -US$66 897 to US$11 896. CONCLUSIONS: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.

• MeSH
• Alzheimer Disease * economics   drug therapy   MeSH
• Cost-Benefit Analysis * MeSH
• Models, Economic MeSH
• Cognitive Dysfunction * economics   MeSH
• Quality-Adjusted Life Years MeSH
• Humans MeSH
• Decision Support Techniques MeSH
• Disease Progression MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

BACKGROUND: Early life socioeconomic disadvantage and adverse experiences may lead to overeating, which is in turn associated with increased body mass index (BMI). However, recent evidence indicated that the association between childhood BMI and overeating might be bidirectional. This bidirectionality prompts the need for further investigation of early life predictors of BMI in childhood. OBJECTIVES: To longitudinally assess the directionality of the association between childhood BMI and perceived overeating and to investigate their antecedent early life predictors. METHODS: The sample included data from 5151 children from the ELSPAC study, collected between 18 months and 11 years of child age. The outcomes were child BMI and mother-reported overeating, assessed at the age of 3, 5, 7 and 11 years. Predictors included maternal BMI, maternal education, single parenthood, financial difficulties and adverse childhood experiences (ACEs) reported by parents and paediatricians. The random intercept cross-lagged panel model was applied. RESULTS: The mean child's BMI at age 3 was 15.59 kg/m2 and increased to 17.86 kg/m2 at age 11. The percentage of parent-reported overeating increased in the following period, from about 12% at age 3 to 17% at age 11. The results showed temporal stability in perceived overeating and BMI, with a bidirectional relationship strengthening over time. The child's BMI was associated with maternal BMI. Maternal BMI was positively associated with child-perceived overeating, but a stronger effect was found for ACEs. ACEs mediated the impact of maternal education, financial difficulties and single parenthood on overeating. CONCLUSIONS: We observed stable bidirectional associations between BMI and perceived overeating. The results indicated two main pathways: one linked to maternal BMI and early childhood BMI increase followed by perceived overeating and the second associated with ACEs mediating the effect of early childhood social factors on perceived overeating, leading to gradual BMI gain.

• MeSH
• Child MeSH
• Hyperphagia * psychology   epidemiology   MeSH
• Body Mass Index * MeSH
• Infant MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Mothers psychology   statistics & numerical data   MeSH
• Adverse Childhood Experiences * statistics & numerical data   psychology   MeSH
• Pediatric Obesity * epidemiology   psychology   MeSH
• Child, Preschool MeSH
• Socioeconomic Factors MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week. METHODS: We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases. RESULTS: Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3-10.8), 17.6 (95% CI 17.3-17.9), and 0.49 (95% CI 0.44-0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77-78), 53 (52-53), and 5 (5-5) per 1000 livebirths. CONCLUSIONS: CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases. IMPACT: In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs.

• MeSH
• Anti-Bacterial Agents * therapeutic use   administration & dosage   MeSH
• Incidence MeSH
• Humans MeSH
• Infant, Premature MeSH
• Infant, Newborn MeSH
• Neonatal Sepsis * drug therapy   diagnosis   MeSH
• Retrospective Studies MeSH
• Sepsis * drug therapy   epidemiology   diagnosis   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Australia MeSH
• Europe MeSH
• North America MeSH

INTRODUCTION: Despite national guidelines and use of intrapartum antibiotic prophylaxis (IAP), Streptococcus agalactiae (group B streptococci (GBS)) is still a leading cause of morbidity and mortality in newborns in Europe and the United States. The European DEVANI (Design of a Vaccine Against Neonatal Infections) program assessed the neonatal GBS infection burden in Europe, the clinical characteristics of colonized women and microbiological data of GBS strains in colonized women and their infants with early-onset disease (EOD). METHODS: Overall, 1083 pregnant women with a GBS-positive culture result from eight European countries were included in the study. Clinical obstetrical information was collected by a standardized questionnaire. GBS strains were characterized by serological and molecular methods. RESULTS: Among GBS carriers included in this study after testing positive for GBS by vaginal or recto-vaginal sampling, 13.4% had at least one additional obstetrical risk factor for EOD. The five most common capsular types (i.e., Ia, Ib, II, III and V) comprised ~ 93% of GBS carried. Of the colonized women, 77.8% received any IAP, and in 49.5% the IAP was considered appropriate. In our cohort, nine neonates presented with GBS early-onset disease (EOD) with significant regional heterogeneity. CONCLUSIONS: Screening methods and IAP rates need to be harmonized across Europe in order to reduce the rates of EOD. The epidemiological data from eight different European countries provides important information for the development of a successful GBS vaccine.

• MeSH
• Antibiotic Prophylaxis MeSH
• Adult MeSH
• Pregnancy Complications, Infectious * epidemiology   microbiology   MeSH
• Humans MeSH
• Young Adult MeSH
• Infant, Newborn MeSH
• Carrier State epidemiology   microbiology   MeSH
• Streptococcus agalactiae * isolation & purification   classification   MeSH
• Streptococcal Infections * epidemiology   microbiology   prevention & control   MeSH
• Pregnancy MeSH
• Vagina microbiology   MeSH
• Infectious Disease Transmission, Vertical statistics & numerical data   prevention & control   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Europe MeSH

Systémová forma juvenilní idiopatické artritidy (sJIA) je charakterizována systémovým zánětem, který se projevuje rekurentní horečkou, kožní vyrážkou, hepatosplenomegalií, lymfadenopatií, serozitidou, artritidou a elevací laboratorních zánětlivých parametrů. Život ohrožující komplikací může být syndrom aktivace makrofágů (macrophage activation syndrome, MAS). Zejména na začátku nemoci se v patogenezi sJIA uplatňuje dysregulace vrozené imunitní odpovědi s nadprodukcí interleukinu 1 (IL-1). Při léčbě blokátory IL-1 je prokázáno významné zlepšení průběhu i prognózy sJIA, a to zejména v případě včasného zahájení léčby. Anakinra, antagonista receptoru pro interleukin 1, je účinným lékem u pacientů se sJIA, což ukazuje i naše kazuistika.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation, which manifests itself with recurrent fever, skin rash, hepatosplenomegaly, lymphadenopathy, serositis, arthritis and elevated inflammatory markers. Macrophage activation syndrome (MAS) can be a life-threatening complication of this disease. Especially at disease onset, the dysregulation in the innate immune response with overproduction of interleukin 1 (IL-1) plays a key role in the pathogenesis of sJIA. Anti-IL-1 therapy significantly improves treatment outcomes and prognosis, particularly when initiated early. Anakinra, an interleukin-1 receptor antagonist, is an effective treatment option for patients with sJIA.

Alzheimerova choroba je nejčastější příčinou demence a včasná diagnostika je klíčová pro zahájení léčby. Porucha čichu, zejména schopnost identifikace pachů, byla opakovaně identifikována jako raný příznak neurodegenerativních změn a může pomoci při časné detekci Alzheimerovy choroby. Psychofyzické testy čichu, jako je Sniffin’ Sticks, (SST) University of Pennsylvania Smell Identification Test (UPSIT), či test parfémovaných fixů (OMT), jsou spolehlivými nástroji pro hodnocení čichových funkcí a mají potenciál doplnit tradiční neuropsychologické testy. Kombinace čichových a kognitivních testů významně zvyšuje přesnost predikce nástupu demence.

Koutná V, Štěpánek L, Trajerová R, Janout V, Janoutová J. Olfactory impairment as a biomarker in early diagnosis of Alzheimer’s disease in primary care Alzheimer’s disease is the most common cause of dementia and early diagnosis is key to initiating treatment. Olfactory dysfunction, particularly the ability to discriminate odors, has been repeatedly identified as an early sign of neurodegenerative changes and may aid in the early detection of Alzheimer’s disease. Psychophysical olfactory tests such as the Sniffin’ Sticks (SST), University of Pennsylvania Smell Identification Test (UPSIT) or the Odorized Marker Test (OMT) are reliable tools for assessing olfactory function and have potential to complement traditional neuropsychological tests. The combination of olfactory and cognitive tests significantly increases the accuracy of predicting the onset of dementia.

Zavedení inhibitorů cyklin dependentní kinázy 4/6 (cyciin-dependent kinase 4/6, CDK4/6) razantním způsobem změnilo způsob léčby metastazujícího karcinomu prsu hormonálně pozitivního (HR+) a karcinomu prsu s negativitou receptoru 2 pro lidský epidermální růstový faktor (human epidermal growth factor receptor 2 negative, HER2-). V našem případě prezentujeme významnou klinickou odpověď u postmenopauzální pacientky s de novo diagnostikovaným metastazujícím karcinomem prsu, která byla léčena kombinací ribociklib, letrozol a denosumab. V průběhu terapie byla úspěšně léčena i hematotoxicita při středně náročném průběhu onemocněním covid-19.

The advent of cyciin-dependent kinase 4 and 6 (CDK4/6) inhibitors has dramatically changed the treatment of metastatic breast cancer-hormone positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-). We present a significant clinical response in a postmenopausal patient with de novo diagnosed metastatic breast cancer who was treated with a combination of ribociclib, letrozole, and denosumab. In the course of the therapy, hematotoxicity was also successfully treated during the moderately demanding course of the COVID-19 disease.