Childhood tuberous sclerosis complex in southern Sweden: a paradigm shift in diagnosis and treatment.

AIM: To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time. METHODS: In this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020. RESULTS: Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care. CONCLUSION: Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.

Left-Handers Are Less Lateralized Than Right-Handers for Both Left and Right Hemispheric Functions.

Many neuroscientific techniques have revealed that more left- than right-handers will have unusual cerebral asymmetries for language. After the original emphasis on frequency in the aphasia and epilepsy literatures, most neuropsychology, and neuroimaging efforts rely on estimates of central tendency to compare these two handedness groups on any given measure of asymmetry. The inevitable reduction in mean lateralization in the left-handed group is often postulated as being due to reversed asymmetry in a small subset of them, but it could also be due to a reduced asymmetry in many of the left-handers. These two possibilities have hugely different theoretical interpretations. Using functional magnetic resonance imaging localizer paradigms, we matched left- and right-handers for hemispheric dominance across four functions (verbal fluency, face perception, body perception, and scene perception). We then compared the degree of dominance between the two handedness groups for each of these four measures, conducting t-tests on the mean laterality indices. The results demonstrate that left-handers with typical cerebral asymmetries are less lateralized for language, faces, and bodies than their right-handed counterparts. These results are difficult to reconcile with current theories of language asymmetry or of handedness.

Conduct disorder and somatic health in children: a nationwide genetically sensitive study.

BACKGROUND: Conduct disorder (CD), a serious behavioral and emotional disorder in childhood and adolescence, characterized by disruptive behavior and breaking societal rules. Studies have explored the overlap of CD with neurodevelopmental problems (NDP). The somatic health of children with NDP has been investigated; however, the prevalence of these problems in children with CD has not been sufficiently studied. Holistic assessment of children with CD is required for establishing effective treatment strategies. AIMS: (1) Define the prevalence of selected neurological problems (migraine and epilepsy) and gastrointestinal problems (celiac disease, lactose intolerance, diarrhea, and constipation) in a population of twins aged 9 or 12; (2) Compare the prevalence of somatic problems in three subpopulations: (a) children without CD or NDP, (b) children with CD, and (c) children with both CD and NDP; (3) Select twin pairs where at least one child screened positive for CD but not NDP (proband) and map both children's neurological and gastrointestinal problems. METHOD: Telephone interviews with parents of 20,302 twins in a cross-sectional, nationwide, ongoing study. According to their scores on the Autism-Tics, AD/HD, and Comorbidities inventory, screen-positive children were selected and divided into two groups: (1) children with CD Only, (2) children with CD and at least one NDP. RESULTS: Children with CD had an increased prevalence of each neurological and gastrointestinal problem (except celiac disease), and the prevalence of somatic problems was further increased among children with comorbid CD and NDP. The presence of CD (without NDP) increased the odds of constipation for girls and the odds of epilepsy for boys. Girls with CD generally had more coexisting gastrointestinal problems than boys with CD. Female co-twins of probands with CD were strongly affected by gastrointestinal problems. Concordance analyses suggested genetic background factors in neurological and gastrointestinal problems, but no common etiology with CD could be concluded. CONCLUSION: Co-occurring NDP could explain most of the increased prevalence of somatic problems in CD. Our results raise a new perspective on CD in children and adolescents; their CD seems to be linked to a number of other health problems, ranging from neurodevelopmental and psychiatric disorders to somatic complaints.

The depth and breadth of multiple perceptual asymmetries in right handers and non-right handers.

Several non-verbal perceptual and attentional processes have been linked with specialization of the right cerebral hemisphere. Given that most people have a left hemispheric specialization for language, it is tempting to assume that functions of these two classes of dominance are related. Unfortunately, such models of complementarity are notoriously hard to test. Here we suggest a method which compares frequency of a particular perceptual asymmetry with known frequencies of left hemispheric language dominance in right-handed and non-right handed groups. We illustrate this idea using the greyscales and colourscales tasks, chimeric faces, emotional dichotic listening, and a consonant-vowel dichotic listening task. Results show a substantial "breadth" of leftward bias on the right hemispheric tasks and rightward bias on verbal dichotic listening. Right handers and non-right handers did not differ in terms of proportions of people who were left biased for greyscales/colourscales. Support for reduced typical biases in non-right handers was found for chimeric faces and for CV dichotic listening. Results are discussed in terms of complementary theories of cerebral asymmetries, and how this type of method could be used to create a taxonomy of lateralized functions, each categorized as related to speech and language dominance, or not.

Adipic acid tolerance screening for potential adipic acid production hosts.

BACKGROUND: Biobased processes for the production of adipic acid are of great interest to replace the current environmentally detrimental petrochemical production route. No efficient natural producer of adipic acid has yet been identified, but several approaches for pathway engineering have been established. Research has demonstrated that the microbial production of adipic acid is possible, but the yields and titres achieved so far are inadequate for commercialisation. A plausible explanation may be intolerance to adipic acid. Therefore, in this study, selected microorganisms, including yeasts, filamentous fungi and bacteria, typically used in microbial cell factories were considered to evaluate their tolerance to adipic acid. RESULTS: Screening of yeasts and bacteria for tolerance to adipic acid was performed in microtitre plates, and in agar plates for A. niger in the presence of adipic acid over a broad range of concentration (0-684 mM). As the different dissociation state(s) of adipic acid may influence cells differently, cultivations were performed with at least two pH values. Yeasts and A. niger were found to tolerate substantially higher concentrations of adipic acid than bacteria, and were less affected by the undissociated form of adipic acid than bacteria. The yeast exhibiting the highest tolerance to adipic acid was Candida viswanathii, showing a reduction in maximum specific growth rate of no more than 10-15% at the highest concentration of adipic acid tested and the tolerance was not dependent on the dissociation state of the adipic acid. CONCLUSIONS: Tolerance to adipic acid was found to be substantially higher among yeasts and A. niger than bacteria. The explanation of the differences in adipic acid tolerance between the microorganisms investigated are likely related to fundamental differences in their physiology and metabolism. Among the yeasts investigated, C. viswanathii showed the highest tolerance and could be a potential host for a future microbial cell factory for adipic acid.

Hemispheric asymmetry of hand and tool perception in left- and right-handers with known language dominance.

Regions in the brain that are selective for images of hands and tools have been suggested to be lateralised to the left hemisphere of right-handed individuals. In left-handers, many functions related to tool use or tool pantomime may also depend more on the left hemisphere. This result seems surprising, given that the dominant hand of these individuals is controlled by the right hemisphere. One explanation is that the left hemisphere is dominant for speech and language in the majority of left-handers, suggesting a supraordinate control system for complex motor sequencing that is required for skilled tool use, as well as for speech. In the present study, we examine if this left-hemispheric specialisation extends to perception of hands and tools in left- and right-handed individuals. We, crucially, also include a group of left-handers with right-hemispheric language dominance to examine their asymmetry biases. The results suggest that tools lateralise to the left hemisphere in most right-handed individuals with left-hemispheric language dominance. Tools also lateralise to the language dominant hemisphere in right-hemispheric language dominant left-handers, but the result for left-hemispheric language dominant left-handers are more varied, and no clear bias towards one hemisphere is found. Hands did not show a group-level asymmetry pattern in any of the groups. These results suggest a more complex picture regarding hemispheric overlap of hand and tool representations, and that visual appearance of tools may be driven in part by both language dominance and the hemisphere which controls the motor-dominant hand.

Brain (Yakovlevian) torque direction is associated with volume asymmetry of the intracranial transverse sinuses: evidence from situs inversus totalis.

Previous research reported reversal of the prototypical brain torque in individuals with mirrored visceral topology (situs inversus totalis, SIT). Here, we investigate if typical asymmetry of the posterior intracranial venous system is also reversed in SIT and whether the direction and magnitude of this asymmetry is related to the direction and magnitude of the brain torque. Brain structural MRI images of 38 participants with SIT were compared with those of 38 matched control participants. Occipital and frontal petalia and bending were measured using a standardized procedure. In addition, representative sections of the left and right transverse sinuses were segmented, and their respective volumes determined. Participants with SIT showed general reversal of occipital and frontal petalia and occipital bending, as well as reversal of typical transverse sinus asymmetry. Transverse sinus volume was significantly correlated with several torque measures, such that the smaller transverse sinus was associated with a larger ipsilateral occipital petalia, contralateral occipital bending, and ipsilateral frontal bending. We propose an anatomical mechanism to explain occipital petalia and bending, and conclude that anatomical constraints imposed by the asymmetry of the posterior venous system provide and additional account to elucidate the formation of the human brain torque.

Cost-Effectiveness Analysis of Adjuvant Olaparib Versus Watch and Wait in the Treatment of Germline BRCA1/2-Mutated, High-Risk, HER2-Negative Early Breast Cancer in Sweden.

INTRODUCTION: This study evaluated the cost effectiveness of adjuvant olaparib versus watch and wait (WaW) in patients with germline breast cancer susceptibility gene 1/2 (gBRCA1/2)-mutated, high-risk, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC), previously treated with neoadjuvant or adjuvant chemotherapy, from a Swedish healthcare perspective. METHODS: A five-state (invasive disease-free survival [IDFS], non-metastatic breast cancer [non-mBC], early-onset mBC, late-onset mBC, death) semi-Markov state transition model with a lifetime horizon was developed. Transition probabilities were informed by data from the Phase III OlympiA trial, supplemented with data from additional studies in BRCA-mutated, HER2-negative mBC. Health state utilities were derived via mapping of OlympiA data and supplemented by literature estimates. Treatment, adverse events and other medical costs were extracted from publicly available Swedish sources. Incremental cost per life-year (LY) and quality-adjusted life-year (QALY) gained were estimated. Costs and outcomes were discounted at 3% annually. One-way deterministic and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: Over a lifetime horizon, adjuvant olaparib was associated with an additional 1.50 LYs and 1.22 QALYs, and incremental cost of 471,156 Swedish krona (SEK) versus WaW (discounted). The resulting ICER was 385,183SEK per QALY gained for olaparib versus WaW. ICERs remained below 1,000,000SEK across a range of scenarios, and were consistent across subgroups (hormone receptor [HR]-positive/HER2-negative and triple-negative breast cancer [TNBC]). In PSA, the probability of olaparib being cost effective at 1,000,000SEK per QALY was 99.8%. CONCLUSIONS: At list price, adjuvant olaparib is a cost-effective alternative to WaW in patients with gBRCA1/2-mutated, high-risk, HER2-negative eBC in Sweden.

Clinical implications of brain asymmetries.

No two human brains are alike, and with the rise of precision medicine in neurology, we are seeing an increased emphasis on understanding the individual variability in brain structure and function that renders every brain unique. Functional and structural brain asymmetries are a fundamental principle of brain organization, and recent research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. In this Review, we provide an overview of brain asymmetries, variations in such asymmetries and their relevance in the clinical context. We review recent findings on brain asymmetries in neuropsychiatric and neurodevelopmental disorders, as well as in specific learning disabilities, with an emphasis on large-scale database studies and meta-analyses. We also highlight the relevance of asymmetries for disease symptom onset in neurodegenerative diseases and their implications for lateralized treatments, including brain stimulation. We conclude that alterations in brain asymmetry are not sufficiently specific to act as diagnostic biomarkers but can serve as meaningful symptom or treatment response biomarkers in certain contexts. On the basis of these insights, we provide several recommendations for neurological clinical practice.

Analysis of distributions reveals real differences on dichotic listening scores between left- and right-handers.

About 95% of right-handers and 70% of left-handers have a left-hemispheric specialization for language. Dichotic listening is often used as an indirect measure of this language asymmetry. However, while it reliably produces a right-ear advantage (REA), corresponding to the left-hemispheric specialization of language, it paradoxically often fails to obtain statistical evidence of mean differences between left- and right-handers. We hypothesized that non-normality of the underlying distributions might be in part responsible for the similarities in means. Here, we compare the mean ear advantage scores, and also contrast the distributions at multiple quantiles, in two large independent samples (Ns = 1,358 and 1,042) of right-handers and left-handers. Right-handers had an increased mean REA, and a larger proportion had an REA than in the left-handers. We also found that more left-handers are represented in the left-eared end of the distribution. These data suggest that subtle shifts in the distributions of DL scores for right- and left-handers may be at least partially responsible for the unreliability of significantly reduced mean REA in left-handers.

Inconsistent language lateralisation - Testing the dissociable language laterality hypothesis using behaviour and lateralised cerebral blood flow.

BACKGROUND: Most people have strong left-brain lateralisation for language, with a minority showing right- or bilateral language representation. On some receptive language tasks, however, lateralisation appears to be reduced or absent. This contrasting pattern raises the question of whether and how language laterality may fractionate within individuals. Building on our prior work, we postulated (a) that there can be dissociations in lateralisation of different components of language, and (b) these would be more common in left-handers. A subsidiary hypothesis was that laterality indices will cluster according to two underlying factors corresponding to whether they involve generation of words or sentences, versus receptive language. METHODS: We tested these predictions in two stages: At Step 1 an online laterality battery (Dichotic listening, Rhyme Decision and Word Comprehension) was given to 621 individuals (56% left-handers); At Step 2, functional transcranial Doppler ultrasound (fTCD) was used with 230 of these individuals (51% left-handers). 108 left-handers and 101 right-handers gave useable data on a battery of three language generation and three receptive language tasks. RESULTS: Neither the online nor fTCD measures supported the notion of a single language laterality factor. In general, for both online and fTCD measures, tests of language generation were left-lateralised. In contrast, the receptive tasks were at best weakly left-lateralised or, in the case of Word Comprehension, slightly right-lateralised. The online measures were only weakly correlated, if at all, with fTCD measures. Most of the fTCD measures had split-half reliabilities of at least .7, and showed a distinctive pattern of intercorrelation, supporting a modified two-factor model in which Phonological Decision (generation) and Sentence Decision (reception) loaded on both factors. The same factor structure fitted data from left- and right-handers, but mean scores on the two factors were lower (less left-lateralised) in left-handers. CONCLUSIONS: There are at least two factors influencing language lateralization in individuals, but they do not correspond neatly to language generation and comprehension. Future fMRI studies could help clarify how far they reflect activity in specific brain regions.

The validity and reliability of quantifying hemispheric specialisation using fMRI: Evidence from left and right handers on three different cerebral asymmetries.

Neuroimaging has tremendous potential for quantifying hemispheric specializations. However, the possibilities remain under-utilized, in part, given some of the complexities in quantifying any differences in a reliable, transparent fashion. A second issue with hemispheric asymmetries is that they are extremely one-sided in most people. This skew limits the generalisability of any findings to those participants with rarer forms of cerebral asymmetry. Here, we demonstrate usefulness of an approach developed by Wilke and Lidzba, (J Neurosci Meth, 163, 2007), which allows for threshold-independent estimates of cerebral asymmetry to be calculated in individual participants. We compared these estimates from two separate runs for three different cerebral asymmetries in the same participants. We circumvented the skewed nature of this type of data in two ways; first, we scanned a large number of non-right handed participants, and second, we included asymmetries that favour the right hemisphere in right handers, which we had reason to believe were less skewed than those related to speech and language. Verbal fluency and two visuoperceptual asymmetries were localized in a sample of 33 right handed and 60 non-right handed participants. Laterality indices (LIs), which quantify the direction and strength of an asymmetry, were calculated for BOLD activity relating to language, face perception, and body perception in each run separately. Run 1 - run 2 correlations were all statistically significant and surprisingly sizeable (r = 0.89 to r = 0.62), considering the relatively short amount of time on task within our particular localizers. This noteworthy success validates a number of useful ways that functional neuroimaging can be used to advance understanding of cerebral asymmetries.

Autoantibodies in Pandemrix®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test.

Study objectives: Narcolepsy type 1 (NT1) is a chronic sleep disorder characterized by loss of hypocretin-producing neurons. Increased NT1 incidence was observed in Sweden following mass-vaccination with Pandemrix®. Genetic association to HLA DQB1*06:02 implies an autoimmune origin, but target autoantigen remains unknown. Candidate autoantigens for NT1 have previously been identified in solid-phase immunoassays, while autoantibodies against conformation-dependent epitopes are better detected in radiobinding assays. The aims are to determine autoantibody levels against nine candidate autoantigens representing (1) proteins of the hypocretin transmitter system; Preprohypocretin (ppHypocretin), Hypocretin peptides 1 and 2 (HCRT1 and HCRT2) and Hypocretin receptor 2 (HCRTR2); (2) proteins previously associated with NT1; Tribbles homologue 2 (TRIB2), Pro-opiomelanocortin/alpha-melanocyte-stimulating-hormone (POMC/α-MSH) and Prostaglandin D2 Receptor DP1 (DP1); (3) proteins suggested as autoantigens for multiple sclerosis (another HLA DQB1*06:02-associated neurological disease); ATP-dependent Inwardly Rectifying Potassium Channel Kir4.1 (KIR4.1) and Calcium-activated chloride channel Anoctamin 2 (ANO2). Methods: Serum from post-Pandemrix® NT1 patients (n = 31) and their healthy first-degree relatives (n = 66) were tested for autoantibody levels in radiobinding assays separating autoantibody bound from free labelled antigen with Protein A-Sepharose. 125I-labelled HCRT1 and HCRT2 were commercially available while 35S-methionine-labelled ppHypocretin, HCRTR2, TRIB2, α-MSH/POMC, DP1, KIR4.1 or ANO2 was prepared by in vitro transcription translation of respective cDNA. In-house standards were used to express data in arbitrary Units/ml (U/ml). Results: All radiolabelled autoantigens were detected in a concentration-dependent manner by respective standard sera. Levels of autoantibodies in the NT1 patients did not differ from healthy first-degree relatives in any of the nine candidate autoantigens. Conclusions: None of the nine labelled proteins proposed to be autoantigens were detected in the radiobinding assays for conformation-dependent autoantibodies. The results emphasise the need of further studies to identify autoantigen(s) and clarify the mechanisms in Pandemrix®-induced NT1.

In silico and in vitro studies of the reduction of unsaturated α,ß bonds of trans-2-hexenedioic acid and 6-amino-trans-2-hexenoic acid - Important steps towards biobased production of adipic acid.

The biobased production of adipic acid, a precursor in the production of nylon, is of great interest in order to replace the current petrochemical production route. Glucose-rich lignocellulosic raw materials have high potential to replace the petrochemical raw material. A number of metabolic pathways have been proposed for the microbial conversion of glucose to adipic acid, but achieved yields and titers remain to be improved before industrial applications are feasible. One proposed pathway starts with lysine, an essential metabolite industrially produced from glucose by microorganisms. However, the drawback of this pathway is that several reactions are involved where there is no known efficient enzyme. By changing the order of the enzymatic reactions, we were able to identify an alternative pathway with one unknown enzyme less compared to the original pathway. One of the reactions lacking known enzymes is the reduction of the unsaturated α,ß bond of 6-amino-trans-2-hexenoic acid and trans-2-hexenedioic acid. To identify the necessary enzymes, we selected N-ethylmaleimide reductase from Escherichia coli and Old Yellow Enzyme 1 from Saccharomyces pastorianus. Despite successful in silico docking studies, where both target substrates could fit in the enzyme pockets, and hydrogen bonds with catalytic residues of both enzymes were predicted, no in vitro activity was observed. We hypothesize that the lack of activity is due to a difference in electron withdrawing potential between the naturally reduced aldehyde and the carboxylate groups of our target substrates. Suggestions for protein engineering to induce the reactions are discussed, as well as the advantages and disadvantages of the two metabolic pathways from lysine. We have highlighted bottlenecks associated with the lysine pathways, and proposed ways of addressing them.

Intensive care nurses' experiences of infants and partners' presence on the postoperative ward after an emergency caesarean section; An interview study.

It is evident that immediate skin-to-skin care after birth has the potential to improve breastfeeding outcomes and maternal satisfaction after a caesarean section; hence partners and infants should be present on the postoperative ward. OBJECTIVE: To investigate the intensive care nurses' experiences of having the infant and partner present on the postoperative ward after emergency caesarean sections. DESIGN: Interviews with semi-structured interviews were conducted and analysed using qualitative content analysis. SETTING: The interviews were conducted at a hospital in Stockholm, Sweden; where close to 10,000 births occur each year. After a caesarean section the mother is treated on a postoperative ward for at least two hours. Eight intensive care nurses participated in the study. RESULT: The analysis yields the theme 'The challenges of caring for infants on a postoperative unit' covering the following categories; collision between the intensive care nurse and midwife, responsibility versus knowledge and organisational issues. The study concluded that improved routines and increased continuity between involved clinics could improve care. There is also a need for education for staff involved in caesarean section regarding the benefits of early skin-to-skin care between the mother and her infant.