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.

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.

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.

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.

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.

Screening human lung cancer with predictive models of serum magnetic resonance spectroscopy metabolomics.

The current high mortality of human lung cancer stems largely from the lack of feasible, early disease detection tools. An effective test with serum metabolomics predictive models able to suggest patients harboring disease could expedite triage patient to specialized imaging assessment. Here, using a training-validation-testing-cohort design, we establish our high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS)-based metabolomics predictive models to indicate lung cancer presence and patient survival using serum samples collected prior to their disease diagnoses. Studied serum samples were collected from 79 patients before (within 5.0 y) and at lung cancer diagnosis. Disease predictive models were established by comparing serum metabolomic patterns between our training cohorts: patients with lung cancer at time of diagnosis, and matched healthy controls. These predictive models were then applied to evaluate serum samples of our validation and testing cohorts, all collected from patients before their lung cancer diagnosis. Our study found that the predictive model yielded values for prior-to-detection serum samples to be intermediate between values for patients at time of diagnosis and for healthy controls; these intermediate values significantly differed from both groups, with an F1 score = 0.628 for cancer prediction. Furthermore, values from metabolomics predictive model measured from prior-to-diagnosis sera could significantly predict 5-y survival for patients with localized disease.

Hippocampus shape characterization with 3D Zernike transformation in clinical Alzheimer's disease progression.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia among older adults. Mild cognitive impairment (MCI) is considered a transitional phase between healthy cognitive aging and dementia. Progressive brain volume reduction/atrophy, particularly of the hippocampus, is associated with the transition from normal to MCI, and then to AD. We aimed to develop methods to characterize the shape of hippocampus and explore its potential as an imaging marker to monitor clinical AD progression. We implemented a 3D Zernike transformation to characterize the shape changes of hippocampus in 428 older subjects with high-quality T1 -weighted volumetric brain scans from the Alzheimer's Disease Neuroimaging Initiative data set (151 normal, 258 MCI, and 19 AD). Over 2 years, 15 cognitively normal subjects converted to MCI, and 42 subjects with MCI converted to AD. We found a significant correlation between hippocampal volume changes and Zernike shape metrics. Before a clinical diagnosis of AD, the shapes of the left and right hippocampi changed slowly. After AD diagnosis, both volume and shape changed rapidly but were uncorrelated to each other. During the transition from a clinical diagnosis of MCI to AD, the shape of the left and right hippocampi changed in a correlated manner but became uncorrelated after AD diagnosis. Finally, the pace of hippocampus shape change was associated with its shape and the subject's age and disease condition. In conclusion, the hippocampus shape features characterized with 3D Zernike transformation, in complement to volume measures, may serve as a novel imaging marker to monitor clinical AD progression.

Carbonic anhydrase seven bundles filamentous actin and regulates dendritic spine morphology and density.

Intracellular pH is a potent modulator of neuronal functions. By catalyzing (de)hydration of CO2 , intracellular carbonic anhydrase (CAi ) isoforms CA2 and CA7 contribute to neuronal pH buffering and dynamics. The presence of two highly active isoforms in neurons suggests that they may serve isozyme-specific functions unrelated to CO2 -(de)hydration. Here, we show that CA7, unlike CA2, binds to filamentous actin, and its overexpression induces formation of thick actin bundles and membrane protrusions in fibroblasts. In CA7-overexpressing neurons, CA7 is enriched in dendritic spines, which leads to aberrant spine morphology. We identified amino acids unique to CA7 that are required for direct actin interactions, promoting actin filament bundling and spine targeting. Disruption of CA7 expression in neocortical neurons leads to higher spine density due to increased proportion of small spines. Thus, our work demonstrates highly distinct subcellular expression patterns of CA7 and CA2, and a novel, structural role of CA7.

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.

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.

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder.

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Polygenic risk provides biological validity for the ICHD-3 criteria among Finnish migraine families.

BACKGROUND: Migraine is diagnosed using the extensively field-tested International Classification of Headache Disorders (ICHD-3) consensus criteria derived by the International Headache Society. To evaluate the criteria in respect to a measurable biomarker, we studied the relationship between the main ICHD-3 criteria and the polygenic risk score, a measure of common variant burden in migraine. METHODS: We used linear mixed models to study the correlation of ICHD-3 diagnostic criteria, underlying symptoms, and main diagnoses with the polygenic risk score of migraine in a cohort of 8602 individuals from the Finnish Migraine Genome Project. RESULTS: Main diagnostic categories and all underlying diagnostic criteria formed a consistent continuum along the increasing polygenic burden. Polygenic risk was associated with the heterogeneous clinical picture starting from the non-migraine headache (mean 0.07; 95% CI 0.02-0.12; p = 0.008 compared to the non-headache group), to probable migraine (mean 0.13; 95% CI 0.08-0.18; p < 0.001), migraine headache (mean 0.17; 95% CI 0.14-0.21; p < 0.001) and migraine with typical visual aura (mean 0.29; 95% CI 0.26-0.33; p < 0.001), all the way to the hemiplegic aura (mean 0.37; 95% CI 0.31-0.43; p < 0.001). All individual ICHD-3 symptoms and the total number of reported symptoms, a surrogate of migraine complexity, demonstrated a clear inclination with an increasing polygenic risk. CONCLUSIONS: The complex migraine phenotype progressively follows the polygenic burden from individuals with no headache to non-migrainous headache and up to patients with attacks manifesting all the features of the ICHD-3 headache and aura. Results provide further biological support for the ICHD-3 diagnostic criteria.

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

A terrestrial planet candidate in a temperate orbit around Proxima Centauri.

At a distance of 1.295 parsecs, the red dwarf Proxima Centauri (α Centauri C, GL 551, HIP 70890 or simply Proxima) is the Sun's closest stellar neighbour and one of the best-studied low-mass stars. It has an effective temperature of only around 3,050 kelvin, a luminosity of 0.15 per cent of that of the Sun, a measured radius of 14 per cent of the radius of the Sun and a mass of about 12 per cent of the mass of the Sun. Although Proxima is considered a moderately active star, its rotation period is about 83 days (ref. 3) and its quiescent activity levels and X-ray luminosity are comparable to those of the Sun. Here we report observations that reveal the presence of a small planet with a minimum mass of about 1.3 Earth masses orbiting Proxima with a period of approximately 11.2 days at a semi-major-axis distance of around 0.05 astronomical units. Its equilibrium temperature is within the range where water could be liquid on its surface.

Production of galactosylated complex-type N-glycans in glycoengineered Saccharomyces cerevisiae.

N-glycosylation is an important posttranslational modification affecting the properties and quality of therapeutic proteins. Glycoengineering in yeast aims to produce proteins carrying human-compatible glycosylation, enabling the production of therapeutic proteins in yeasts. In this work, we demonstrate further development and characterization of a glycoengineering strategy in a Saccharomyces cerevisiae Δalg3 Δalg11 strain where a truncated Man3GlcNAc2 glycan precursor is formed due to a disrupted lipid-linked oligosaccharide synthesis pathway. We produced galactosylated complex-type and hybrid-like N-glycans by expressing a human galactosyltransferase fusion protein both with and without a UDP-glucose 4-epimerase domain from Schizosaccharomyces pombe. Our results showed that the presence of the UDP-glucose 4-epimerase domain was beneficial for the production of digalactosylated complex-type glycans also when extracellular galactose was supplied, suggesting that the positive impact of the UDP-glucose 4-epimerase domain on the galactosylation process can be linked to other processes than its catalytic activity. Moreover, optimization of the expression of human GlcNAc transferases I and II and supplementation of glucosamine in the growth medium increased the formation of galactosylated complex-type glycans. Additionally, we provide further characterization of the interfering mannosylation taking place in the glycoengineered yeast strain. KEY POINTS: • Glycoengineered Saccharomyces cerevisiae can form galactosylated N-glycans. • Genetic constructs impact the activities of the expressed glycosyltransferases. • Growth medium supplementation increases formation of target N-glycan structure.

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

OBJECTIVES: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. MATERIALS AND METHODS: This prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. RESULTS: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. CONCLUSIONS: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction.

COX16 is involved in the biogenesis of cytochrome-c-oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain. We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by Western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild-type COX16 complementary DNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease.

Sarcopenic Obesity and its Prognostic Impact on Urological Cancers: A Systematic Review.

PURPOSE: Sarcopenia, an age-related loss of muscle mass and function, may predict adverse outcomes for patients with urological cancers. However, the clinical implications and significance of sarcopenic obesity are not well understood. We systematically reviewed data on the prevalence and prognostic impact of sarcopenic obesity for patients with renal cell carcinoma, urothelial carcinoma and prostate cancer undergoing treatment. MATERIALS AND METHODS: We searched EMBASE®, PubMed®/MEDLINE® and Scopus® for relevant original articles and abstracts published between January 2010 and February 2021. Primary outcomes were overall survival (OS), cancer-specific survival (CSS) and progression-free survival. The secondary outcome was the prevalence of sarcopenic obesity. RESULTS: A total of 15 studies comprising 3,866 patients were included. Of the 10 studies that evaluated survival outcomes, the association between sarcopenic obesity and survival was mixed. One of 10 studies showed a significant association of sarcopenic obesity with OS (HR 0.7, 95% CI 0.51-0.98; p=0.04). One additional study showed reported a trend for shorter OS (p=0.05) associated with sarcopenic obesity. Others reported that it is an adverse prognostic factor for CSS (HR 5.0, 95% CI 1.4-16.7; p=0.01). All other studies did not demonstrate that sarcopenic obesity was of prognostic relevance with regard to OS, CSS and progression-free survival. Overall, its mean prevalence was 27% (range 11-63). CONCLUSIONS: There is considerable heterogeneity in methods used to define sarcopenic obesity in the literature, and current data are limited. Future studies are needed to further understand the relationship of obesity and sarcopenia on the clinical trajectory of patients with urological cancer.