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Introduction:Congenital heart defects (CHDs) are the most common congenital malformations. Patients with CHD have a higher morbidity and mortality rate and are at greater risk for infectious diseases. The risk might even be higher if complex CHD occurs and if CHD is associated with additional co-morbidities. Therefore, immunisations in these children are essential.Materials and Methods:Individuals were recruited at the outpatient centre of the Department of Congenital Heart Defects and Pediatric Cardiology at the German Heart Center Munich in the time between February 2016 and February 2017. Included were children between 23 months and 17 years and a diagnosis of CHD. The vaccination certificate aimed to assess the immunization status.Results:In total, 657 children with CHD were included and analysed. Regarding primary immunisation, only 34 % (n = 221) of the children reached the complete vaccination status within the allowed catch-up time. Among these primary immunisation rates, vaccinations against Hepatitis B, Meningococci, Varicella and Pneumococci were found to have the lowest coverage with all being below 80%. The vaccination rate was partly influenced by the previously performed number of surgeries but not by the diagnosis of specific genetic diseases. At the age of school entry, the immunisation rate in children with CHD was also lower than in the comparable healthy population.Conclusion:The vaccination coverage rate in children with CHD is lower than in comparable healthy children, although this is a vulnerable patient group. Further education of parents and treating physicians of children with CHD regarding vaccination is still needed.

Bei einem Einsatz von Lasern in der Medizin sollte man ein grundlegendes Verstandnis fur dessen physikalischen Eigenschaften haben, um den biologischen Effekt verstehen und abschatzen zu konnen. Die wichtigsten Parameter sind die Art der Energieabgabe, die Wellenlange und die ausgestrahlte Energie – gemessen in Watt. Gepulste Laser kann man in der Therapie von Steinen und Weichgewebe einsetzen, wobei das in der Urologie im Wesentlichen fur die Prostata gilt, in geringerem Mase auch im Harnleiter, in der Harnrohre, der Blase und der Niere.

BACKGROUND: Continuous saline bladder irrigation (CBI) is a common procedure after transurethral surgery and to treat gross hematuria. We conducted this study to gather data on parameters of CBI, medical staff’s work load associated with CBI monitoring, patients’ feeling of safety and of patients’ impairments during CBI. METHODS: We observed CBI taking place after transurethral surgery for a 2–9-hour period. Patients were asked to rank how safe they felt, general impairments and impaired mobility. Irrigation parameters and complications were documented at least every 30 minutes. The staff’s workload was evaluated through the frequency of visits and presence time. RESULTS: The patients’ mobility was notably reduced with an average of 10.5%±16.7% of time spent outside of bed, pain was low (mean 0.60±1.15). Patients felt very safe with CBI (8.8±1.9), hardly impaired overall (3.8±3.0), but restricted in mobility (5.9±2.8). Pain was associated with general impairment and impaired mobility. Clot retention occurred in 5 patients. Average irrigation speed was 9.46±8.69 mL/min (0 to 86.7 mL/min). Urine bags were emptied on average every 2.2±1.2 hours. Patients were visited by medical personnel 1 to 11 times. CONCLUSIONS: CBI remains an improvable procedure in terms of the irrigation process itself to prevent complications, the patients’ feeling of safety and comfort during CBI and the amount of work associated with its monitoring. We have provided parameters for the implementation of more individualized CBI monitoring. TRIAL REGISTRATION: German Clinical Trial Registry; DRKS00023707; Registered retrospectively November 25 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023707

BackgroundATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) inATAD3Alead to neurological syndromes in humans.MethodsTo expand the mutational spectrum ofATAD3Avariants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) inATAD3Ain individuals with neurological and mitochondrial phenotypes. ADrosophila Atad3a Gal4knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants.ResultsWe report 13 individuals from 8 unrelated families with biallelicATAD3Avariants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated withATAD3Apathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy.Drosophilastudies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles.ConclusionOur findings expand the allelic spectrum ofATAD3Avariants and exemplify the use of a functional assay inDrosophilato aid variant interpretation.

Purpose: We evaluated a system for noninvasive quantitative motion tracking to recognize differences in the movement pattern of experienced surgeons and beginners. Since performing endoscopic procedures requires extensive training, and tissue damage due to disruptive movements with sudden acceleration is possible, the learning curve for beginners is of clinical relevance. Steepening this curve may improve patient outcome. Materials and Methods: We used a commercial gyroscope sensor with a wireless data link, which was attached to the resectoscope handle (RH). After recording, orientation was retrieved by application of the calculated rotation matrices to the RH vector relative to the sensor under the boundary condition of rotational movement around and quasi-constant distance to the pivot point at pelvic floor level. Data alignment, normalization, interpolation, and analysis were performed in custom software scripts. Results: Experienced surgeons and beginners were recorded in n = 36 and n = 14 holmium laser enucleation of the prostate (HoLEP), respectively. Prostate size, patient age, and recorded procedure duration were comparable. Mean lever angle of the individual normalized motion patterns was considerably lower (19.28 ± 0.54° [SEM]) in the advanced than in the beginners’ group (24.52 ± 1.00°; p = 0.0001). Further parameters such as velocity and motion variation demonstrated additional differences between both groups. Conclusions: We demonstrate the feasibility of motion tracking in HoLEP. Pronounced differences exist between different stages of surgeon experience with this procedure. The method can easily be adopted to aide young surgeons in resectoscope handling and identification of improvable motion patterns. Damage to the pelvic floor and surrounding tissue may thus be reduced.

Purpose To perform a bibliometric analysis of lased-based BPH treatment publications and to obtain an understanding of the publication trends over time. Materials and methods The Medline database was searched for articles in English language regarding laser-based BPH therapy up to 2018. Matching articles were assigned to at least one of the following categories: Ho:YAG, Tm:YAG, green light, diode, Nd:YAG laser and review articles. The laser categories were analysed using bibliometric procedures regarding citation rate, authors, country of origin and journal of publication. Moreover, the articles on laser BPH therapy included in the EAU, AUA and JUA guidelines were analysed to evaluate the most influential articles. Results In total, 982 articles were included: 317 articles were assigned to green light, 283 to Ho:YAG, 101 to Tm:YAG, 74 to Nd:YAG and 39 to diode lasers. The publication rate for Nd:YAG laser has declined, but continues to grow for Ho:YAG and Tm:YAG lasers. We found a positive correlation between number of authors and year of publication (R = 0.3, p Conclusion Laser-based approaches for BPH treatment are increasing but have not been implemented worldwide. Asia’s contribution should be acknowledged. An inflationary trend regarding the number of authors per article is confirmed.

In den letzten Jahren wurden neue operative Techniken zur Behandlung des benignen Prostatasyndroms (BPS) in die urologische Praxis eingefuhrt und in klinischen Studien evaluiert, mit denen Komplikationen der Standardverfahren (z. B. transurethrale Resektion der Prostata, TURP) vermieden und dennoch gleichwertige klinische Ergebnisse erzielt werden sollen. Im Vordergrund steht der Erhalt der erektilen Funktion und der antegraden Ejakulation. Auserdem sind ambulante Verfahren wunschenswert, die eine rasche Rekonvaleszenz ermoglichen. Diese Arbeit stellt Interventionsablauf, Wirkweise und aktuelle klinische Evidenz fur neue mechanische Ansatze einer Desobstruktion, wassergestutzte Ablationsverfahren und die Prostataarterienembolisation vor. Studienergebnisse deuten teilweise an, dass kunftig nahezu jedem Patienten eine individualisierte Operationstechnik angeboten werden kann, die bei minimiertem Komplikationsrisiko eine optimale symptomatische und funktionelle Verbesserung mit sich bringt.

Background Most cases of lymphoedema are secondary to other causes, while cases of primary lymphoedema, in particular that of congenital origin, are uncommon. Limited genetic disorders are so far known to be associated with lymphatic malformation including mutations in RASA1. This clinical case highlights the possible complications of RASA1-associated lymphatic malformation in a female suffering from recurrent life-threatening septic lymphangitis. Case summary A 23-year-old female patient presented with congenital lymphoedema of the lower right extremity. At the age of eight, she first suffered from an episode of lymphangitis. Thereafter, she developed recurrent episodes of lymphangitis predominately occurring during menstruation and culminating into severe and life-threatening septicaemias. Due to the menstrual association, endometriosis was suspected but could not be confirmed. Furthermore, angiography could not detect any sign of arteriovenous fistula. Single-Photon-Emission-Computed-Tomography confirmed absent major lymphatics of the right leg with severely impaired and prolonged dermal lymphatic backflow. Genetic testing identified a disease-causing variant in the RASA1 gene. Discussion To our knowledge, this is the first case of recurrent septic lymphangitis with close relation to menstruation in a female with RASA1-associated lymphatic malformation. Due to the possible de novo or somatic origin of a pathogenic variant, a genetic disease should be considered in spite of an unremarkable family history or a localized lymphoedema. Although there is no curative therapy available yet, the knowledge of the underlying genetic defect is important for interdisciplinary patient care and might be crucial for individual molecular therapies in the future.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The most dangerous life-threatening symptoms of CVD are myocardial infarction and stroke. The causes of CVD are not entirely clear, and new therapeutic targets are still being sought. One of the factors involved in CVD development among vascular damage and oxidative stress is chronic inflammation. It is known that hyaluronic acid plays an important role in inflammation and is regulated by numerous stimuli, including proinflammatory cytokines. The main receptors for hyaluronic acid are CD44 and RHAMM. These receptors are membrane proteins that differ in structure, but it seems that they can perform similar or synergistic functions in many diseases. Both RHAMM and CD44 are involved in cell migration and wound healing. However, their close association with CVD is not fully understood. In this review, we describe the role of both receptors in CVD.

It has been a year since the coronavirus disease 2019 (COVID-19) was declared pandemic and wreak havoc worldwide. Despite meticulous research has been done in this period, there are still much to be learn from this novel coronavirus. Globally, observational studies have seen that majority of the patients with COVID-19 have preexisting hypertension. This raises the question about the possible relationship between COVID-19 and hypertension. This review summarizes the current understanding of the link between hypertension and COVID-19 and its underlying mechanisms.

Variants in GABRA1 have been associated with different epilepsies ranging from mild generalized forms to epileptic encephalopathies. Despite the broad clinical spectrum, phenotypes were found to be largely concordant within families. Contrary to this observation, we report monozygotic twin sisters with generalized epilepsy due to the c.541C>T; p.(Pro181Ser) de novo variant in GABRA1. One experienced juvenile absence seizures promptly responding to first‐line medication, whereas the second developed severe treatment‐refractory epilepsy with febrile, absence, atonic, and tonic‐clonic seizures indicating marked intrafamilial variability in GABRA1‐related epilepsy. Moreover, we provide a molecular characterization of the novel variant based on recently published structural data.

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

BackgroundThe ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.ObjectiveTo expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles.MethodsExome sequencing was used to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3A Gal4 trap null allele was generated using CRISPR-Cas9 genome editing technology to aid interpretation of variants.ResultsWe report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. Four of the identified missense variants, p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val), were inherited in trans to loss-of-function alleles. A fifth missense variant, p.(Arg327Pro), was homozygous. Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, and Arg327Pro are severe loss-of-function alleles leading to early developmental lethality and neurogenesis defects, whereas Leu77Val and Arg170Trp are partial loss of function alleles that cause progressive locomotion defects. Moreover, Leu77Val and Arg170Trp expression leads to an increase in autophagy and mitophagy in adult muscles.ConclusionOur findings expand the allelic spectrum of ATAD3A variants, and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)���positive and HPV���negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue���saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV���positive and HPV���negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer���testis antigens, 5 cancer���retina antigens and 8 oncogenes) and 29 HPV���antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV���positive and 209 HPV���negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c���myc, LAGE���1, MAGE���A1, ���A3, ���A4, NY���ESO���1, SpanX���a1 and p53. AR to MAGE���A3, MAGE���A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ���10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue���sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV���positive and HPV���negative HNSCC. �� In Copyright http://rightsstatements.org/vocab/InC/1.0/, What's new? Head and neck squamous cell carcinoma remains a deadly disease but new immunotherapeutic approaches are underexplored. Here the authors tested for antibody responses against human antigens to characterize the expression of such antigens in tumors positive or negative for human papillomavirus (HPV). Antibody responses were significantly different in prevalence and pattern based on HPV���status in a large patient cohort. The authors urge independent confirmation of their results but point out that multiplex serology of tumor antigens could be a promising strategy to identify immunotherapeutic targets based on HPV status., publishedVersion

Background: The amyloid cascade hypothesis characterizes the stereotyped progression of pathological changes in Alzheimer’s disease (AD) beginning with beta amyloid deposition, but does not address the reasons for amyloid deposition. Brain areas with relatively higher neuronal activity, metabolic demand, and production of reactive oxygen species in earlier life may have higher beta amyloid deposition in later life. The aim of this study was to investigate early life patterns of perfusion and late life patterns of amyloid deposition to determine the extent to which normative cerebral perfusion predisposes specific regions to future beta amyloid deposition. Materials and Methods: One hundred twenty-eight healthy, older human subjects (age: 56–87 years old; 44% women) underwent positron emission tomography (PET) imaging with [ 11 C]PiB for measures of amyloid burden. Cerebral perfusion maps derived from 47 healthy younger adults (age: 22–49; 47%) who had undergone single photon emission computed tomography (SPECT) imaging, were averaged to create a normative template, repre- sentative of young, healthy adults. Perfusion and amyloid measures were investigated in 31 cortical regions from the Hammers atlas. We examined the spatial relationship between normative perfusion patterns and amyloid pathophysiology. Results: The pattern of increasing perfusion (temporal lobe < parietal lobe < frontal lobe < insula/cingulate gyrus < occipital lobe; F(4,26) = 7.8, p = 0.0003) in young, healthy adults was not exactly identical to but approximated the pattern of increasing amyloid burden (temporal lobe < occipital lobe < frontal lobe < parietal lobe < insula/cingulate gyrus; F(4,26) = 5.0, p = 0.004) in older adults. However, investigating subregions within cortical lobes provided consistent agreement between ranked normative perfusion patterns and expected Thal staging of amyloid progression in AD (Spearman r = 0.39, p = 0.03). Conclusion: Our findings suggest that brain areas with normatively greater perfusion may be more susceptible to amyloid deposition in later life, possibly due to higher metabolic demand, and associated levels of oxidative stress and inflammation.

Objectives: Due to the increasing fragility of the instruments and rising concerns about the sterility of reprocessable scopes, several single-use devices for flexible ureteroscopy have been introduced. In this study, we compare currently available disposable digital and fiberoptic flexible ureteroscopes with a contemporary reusable fiberoptic device. Materials and Methods: LithoVue™, Pusen Uscope® (UE3011, UE3022), Flexor®Vue™, and a reusable fiber optic flexible ureteroscope (BOA vision®) were tested in kidney models. The setup included (1) visualization of all calices (correct assignment of colored pearls) and (2) the extraction of human calculi with a standard disposable extraction device (NGage®). We documented the effective visualization, stone extraction, and times to completion. In addition, the surgeons' workload and performance were determined using the National Aeronautics and Space Administration-Task Load Index. Results: In visualizing and identifying calices, the LithoVue and both generations of the Uscope performed similarly, but time to completion was significantly longer for all single-use devices in comparison with the Boa Vision. LithoVue retracted stones almost as well as the reusable scope (97% vs 95%/82%/96% stone clearance), while accessibility was impeded using Uscope UE3011, as reflected by the retrieval time per stone (73 vs 102 seconds/stone). This disadvantage has, however, been overcome with the new Uscope Generation UE3022, showing a retrieval time of only 65 seconds per stone, excelling over the reusable scope in this category. The Uscope UE3022 image quality was also rated best, but showed no significant difference. Conclusions: In comparison with disposable ureteroscopes available, LithoVue offers performance and characteristics similar to a reusable device, while the FlexorVu's performance does not yet yield satisfactory results for clinical use. The first generation of Uscope exhibits potential, but requires further technical improvements to match the performance of a reusable device. With the new-generation UE3022, Pusen has made significant improvement and offers a quality comparable with the LithoVue's.

Summary Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. Funding Else Kroner-Fresenius-Stiftung, Technische Universitat Munchen, Helmholtz Zentrum Munchen, Medizinische Universitat Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH). Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS. © 2019, American College of Medical Genetics and Genomics. Dietmar Hopp Stiftung: 23011235 Wellcome Trust: 210585/B/18/Z Jeffrey Modell Foundation S163/10052/2018 We thank Yoo-Mi Kim for providing additional, updated clinical information on patients NBAS 42 and NBAS 43 and John Christodoulou and Shanti Balasubramaniam for providing additional, updated clinical information on patient NBAS 63. Anne Davit Spraul is acknowledged for genetic diagnosis of patients NBAS 46 and NBAS 82, Oanez Ackermann and Dalila Habes are acknowledged for follow-up and Philippe Yakonowsky for his contribution to data collection of these patients. We thank Selina Wächter and Caterina Terrile for excellent technical assistance and Katharina Mayerhanser for organizational support. C.S. is supported by the Dietmar Hopp Foundation, St. Leon-Rot, Germany (grant number 23011235). D.L. is supported by the Deutsche Leberstiftung (grant number S163/10052/2018). J.A.C. is supported in part by the Jeffrey Model Foundation. R.B.R. and G.D.D. are supported by the Wellcome Trust grant 210585/B/18/Z (Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies).

Background Genes encoding cardiac ion channels or regulating proteins have been associated with the inherited form of long QT syndrome (LQTS). Complex pathophysiology and missing functional studies, however, often bedevil variant interpretation and classification. We aimed to evaluate the rate of change in variant classification based on current interpretation standards and dependent on clinical findings. Methods Medical charts of children with a molecular genetic diagnosis of LQTS presenting at our centers were retrospectively reviewed. Reinterpretation of originally reported variants in genes associated with LQTS was performed based on current knowledge (March 2019) and according to the “Standards and Guidelines for the Interpretation of Sequence Variants” by the ACMG 2015. Results About 84 distinct (likely) pathogenic variants identified in 127 patients were reinterpreted. In 12 variants (12/84, 14.3%), classification changed from (likely) pathogenic to variant of unknown significance (VUS). One of these variants was a hypomorphic allele escaping the standard variant classification. Individuals with variants that downgraded to VUS after reevaluation showed significantly lower Schwartz scores and QTc intervals compared to individuals with unchanged variant characterization. Conclusion This finding confirms genetic variant interpretation as a dynamic process and underlines the importance of ongoing genetic counseling, especially in LQTS patients with minor clinical criteria.

Many genetic and nongenetic causes for developmental delay in childhood could be identified. Often, however, the molecular basis cannot be elucidated. As next-generation sequencing is becoming more frequently available in a diagnostic context, an increasing number of genetic variations are found as causative in children with developmental delay.We performed trio exome sequencing in a girl with developmental delay and minor dysmorphological features. Using a filter for de novo variants, the heterozygous missense variant c.812A>T, p.(Glu217Val) was found in the candidate gene POU3F2 in our patient. POU3F2 plays an important role in neuronal differentiation and hormonal regulation. To date, it has not been associated with monogenic disorders. Studies on Pou3f2 knockout mice highlighted the importance of this protein in the development of the brain. Furthermore, microdeletions with an overlapping region including only POU3F2 and FBXL4 were linked to developmental delay in six unrelated families. Therefore, POU3F2 is a strong candidate gene for developmental delay, although functional assays proving this assumption still have to be done.

Homozygous loss-of-function variants in MYO18B have been associated with congenital myopathy, facial dysmorphism and Klippel-Feil anomaly. So far, only four patients have been reported. Comprehensive description of new cases that help to highlight recurrent features and to further delineate the phenotypic spectrum are still missing. We present the fifth case of MYO18B-associated disease in a newborn male patient. Trio exome sequencing identified the previously unreported homozygous nonsense variant c.6433C>T, p.(Arg2145*) in MYO18B (NM_032608.5). While most phenotypic features of our patient align with previously reported cases, we describe the prenatal features for the first time. Taking the phenotypic description of our patient into account, we propose that the core phenotype comprises a severe congenital myopathy with feeding difficulties in infancy and characteristic dysmorphic features.

The aim of the study was to evaluate the feasibility and safety of combining prostatic urethral lift (PUL) and a limited resection of the prostatic middle lobe or bladder neck incision in the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Twenty-eight patients were treated at two tertiary centers and followed prospectively. Patient evaluations included patient characteristics, relief of LUTS symptoms, erectile and ejaculatory function, continence, operative time and adverse events. Patients were followed for a mean of 10.9 months. Patient characteristics were as follows: age 66 years (46–85), prostate volume 39.6 cc (22–66), preoperative IPSS/AUASI 20 (6–35)/QoL 3.9 (1–6)/peak flow 10.5 mL/s (4.0–19)/post-void residual volume (PVR) 123 mL (0–500). Mean operating time was 31 min (9–55). Postoperative complications were minor except for the surgical retreatment of one patient for blood clot retention (Clavien 3b). One patient required catheterization due to urinary retention. Reduction of symptoms (IPSS − 59.6%), increase in QoL (+ 49.0%), increase in flow (+ 111.5%), and reduction of PVR (− 66.8%) were significant. Antegrade ejaculation was always maintained. Our data suggest that a combination of PUL and transurethral surgical techniques is feasible, safe, and effective. This approach may be offered to patients with moderate size prostates including those with unfavorable anatomic conditions for PUL. This procedure is still ‘minimally invasive’ and preserves sexual function. In addition, it may add to a higher functional efficacy compared to PUL alone. DRKS00008970.

Background and purpose A pipeline for fully automated segmentation of 3T brain MRI scans in multiple sclerosis (MS) is presented. This 3T morphometry (3TM) pipeline provides indicators of MS disease progression from multichannel datasets with high-resolution 3-dimensional T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery (FLAIR) contrast. 3TM segments white (WM) and gray matter (GM) and cerebrospinal fluid (CSF) to assess atrophy and provides WM lesion (WML) volume. Methods To address nonuniform distribution of noise/contrast (eg, posterior fossa in 3D-FLAIR) of 3T magnetic resonance imaging, the method employs dual sensitivity (different sensitivities for lesion detection in predefined regions). We tested this approach by assigning different sensitivities to supratentorial and infratentorial regions, and validated the segmentation for accuracy against manual delineation, and for precision in scan-rescans. Results Intraclass correlation coefficients of .95, .91, and .86 were observed for WML and CSF segmentation accuracy and brain parenchymal fraction (BPF). Dual sensitivity significantly reduced infratentorial false-positive WMLs, affording increases in global sensitivity without decreasing specificity. Scan-rescan yielded coefficients of variation (COVs) of 8% and .4% for WMLs and BPF and COVs of .8%, 1%, and 2% for GM, WM, and CSF volumes. WML volume difference/precision was .49 ± .72 mL over a range of 0-24 mL. Correlation between BPF and age was r = .62 (P = .0004), and effect size for detecting brain atrophy was Cohen's d = 1.26 (standardized mean difference vs. healthy controls). Conclusions This pipeline produces probability maps for brain lesions and tissue classes, facilitating expert review/correction and may provide high throughput, efficient characterization of MS in large datasets.

The development of alcohol dependence and depression is determined by various genetic and environmental factors. In the presented study, we used high analgesia (HA) and low analgesia (LA) mouse lines, characterized by different endogenous opioid system activity and divergent blood–brain barrier permeability, to determine the influence of cross-fostering of these lines raised by surrogate mothers on ethanol consumption and development of depressive-like behaviors. We also investigated ethanol drinking by biological parents or surrogate mothers. Furthermore, we investigated whether these parental changes would alter the effect of naloxone on ethanol intake and depressive-like behaviors in offspring. Our results reveal that cross-fostering of HA and LA raised by surrogate mothers has a greater impact on depressive-like behaviors than ethanol consumption. Ethanol intake by biological parents substantially affected depressive-like behaviors and ethanol consumption in offspring. Moreover, ethanol intake by biological parents or an adoptive mother modified the effect of naloxone on ethanol consumption and preference and depressive-like behaviors in the HA offspring only. Together, these results indicate that cross-fostering differentially affects the effect of naloxone on alcohol consumption and the development of depression.

The clinical term “prostatitis” refers to a clinical syndrome defined by the following 4 distinct entities: acute bacterial prostatitis (category 1), chronic bacterial prostatitis (category 2), chronic prostatitis/chronic pelvic pain syndrome (category 3), and asymptomatic prostatitis (category 4) The etiology of the chronic forms is still not fully understood and choice of therapy is often debated. The objective of this systematic review is to collect evidence on the surgical treatment of the chronic form of prostatitis and to evaluate its clinical implication. We performed a systematic literature search and identified 6683 relevant publications, of which 16 were included in the review. Transurethral prostate resection was performed in 110 patients; 78 patients (70%) were reported as “cured”, 16 patients (15%) as improved, and 16 patients (15%) as unchanged. Radical prostatectomy was performed in 21 patients; a full resolution of prostatitis related symptoms was reported for 20 patients (95%). No increased rates of complications or unusual complications were noted. Surgical therapy of chronic bacterial prostatitis or chronic pelvic pain syndrome might be a viable option; however, since little evidence is currently available and no randomized controlled trials have been conducted, the presently available data does not provide a base for clinical decisions.

Microdeletion 1q44 on the long arm of chromosome 1 leads to a phenotype that includes microcephaly, seizure, agenesis or hypogenesis of the corpus callosum, polydactyly, congenital heart defects and severe developmental delay along with characteristic facial dysmorphic signs. Until today, the distinct genetic causes for the different symptoms remain unclear. We here report a 1.2Mb de novo microdeletion 1q44 identified by performing a SNP array analysis. The female patient presented with microcephaly, seizure, hypogenesis of corpus callosum, postaxial hexadactyly, an atrial septal defect, a ventricular septal defect, hypertelorism, a long and smooth philtrum, thin vermilion borders, and micrognathia, all common features of microdeletion 1q44. An additionally performed chromosome analysis excluded any chromosomal rearrangements. The deleted region included the genes ZBTB18 as well as HNRNPU amongst others. Both are possibly candidate genes for the dysgenesis of the corpus callosum. AKT3, another candidate gene, was not affected by the deletion in this patient. Thus, the genetic findings in this case report spotlight ZBTB18 and HNRNPU in the genesis of the typical microdeletion 1q44 symptoms, especially concerning the dysgenesis of the corpus callosum, and therefore could help to unveil more of the genetic background of this syndrome.

To evaluate a recently reported new bioadhesive system for the retrieval of small residual fragments (RFs) after intracorporeal lithotripsy, we systematically compared this system with coagulum lithotomy in retrograde intrarenal surgery.We extracted 30 human stone fragments (≤1 mm) in an ex vivo porcine kidney model using a flexible ureteroscope for three groups: (1) the novel bioadhesive, (2) autologous blood as a natural adhesive, and (3) (control group) a conventional retrieval basket. Each group consisted of 15 test runs. Outcomes were evaluated regarding the macroscopic stone-free rate (SFR), retrieval time, and number of ureteral passages.For groups 1 and 2, a significant advantage in stone clearance, mean retrieval time, and number of retrievals was detected compared to the control group (p = 0.001). The time and number of retrievals were significantly lower in group 1 (10:36 minutes, p = 0.001) than in group 2 (26:12 minutes, p = 0.001), with shorter clotting time and better visibility.These data show the general feasibility of intrarenal RF embedding to improve the SFR. Our data furthermore suggest the superiority of the artificial bioadhesive embedding agent over the application of native blood. Further in vivo studies and other research are necessary to confirm the adhesive's effect in patients.

Developmental and epileptic encephalopathies are characterized by infantile seizures and psychomotor delay. Glycosylphosphatidylinositol biosynthesis defects, resulting in impaired tethering of various proteins to the cell surface, represent the underlying pathology in some patients. One of the genes involved, PIGP, has recently been associated with infantile seizures and developmental delay in two siblings. Here, we report the second family with a markedly overlapping phenotype due to a homozygous frameshift mutation (c.456delA;p.Glu153Asnfs*34) in PIGP. Flow cytometry of patient granulocytes confirmed reduced expression of glycosylphosphatidylinositol‐anchored proteins as functional consequence. Our findings corroborate PIGP as a monogenic disease gene for developmental and epileptic encephalopathy.

Ureteral stenting is a widely used method for noninvasive urinary drainage in ureteral obstruction. However, biofilm development due to transient bacteriuria can cause severe complications such as incrustation with subsequent obstruction as well as recurrent urinary tract infection. Apart from local ailment such as dysuria, this increases both stent replacement frequency and incidence of complications. In this work, we investigated in vitro the bacterial adhesion to a surface-attached and cross-linked poly(N,N-dimethylacrylamide) (PDMAA) hydrogel network, which is known for its nonfouling and protein-repellent characteristics.To mimic the conditions encountered in vivo, PDMAA-coated and uncoated cyclic olefin polymer (COP) slides as well as polyurethane (PU)-coated glass slides were incubated in sterile human urine for 48 hours. Colonization was then simulated by adding known uropathogens, cultivated from clinical urine samples (such as Escherichia coli). After further incubation for 24 and 48 hours, slides were washed, and the remaining adherent bacteria were solubilized by ultrasound. CFUs were counted after plating and incubation for 48 hours of the resulting solution.PDMAA reduced adherent E. coli about fivefold on coated PU glass slides as well as in PDMAA-coated COP slides. With adherent Enterococcus faecalis and Klebsiella pneumoniae there was a tendency to decreased biofilm formation, but the difference was not statistically significant.PDMAA reduces surface adherence of the most common uropathogen significantly. Assessment of clinical relevance and of the effect on further uropathogens needs further experimental and clinical evaluations. German Clinical Trial Register ID: DRKS00013264 (approved WHO primary register).

To assess stone-related events (SREs) requiring retreatment in a series of 100 consecutive patients treated by retrograde intrarenal surgery (RIRS) for renal stones and to evaluate potential risk factors thereof.The primary outcome was incidence of SRE (medical or surgical treatment). Secondary outcomes included side of SRE, time to SRE, and late complications. Analysis of potential risk factors included high-risk stone formers (HRSFs), obesity, high stone burden, and lower pole stones. In addition, we evaluated endoscopically determined small residual fragments (SRF) of1 mm (i.e., fragments too small for retrieval) as an independent risk factor.Eighty-five of the 99 patients were followed up for a mean of 59 months (31-69), among whom 26 (30.1%) had SRE. Thirty-four of the 85 (40%) patients were HRSFs, 22 of whom experienced SRE (both sides) during follow-up (64.7%, p 0.001). Eight of the 17 patients (47.1%) with SRF experienced ipsilateral side SRE compared with 13 (19.1%) of the 68 without SRF (p = 0.022, hazard ratio 2.823, 95% confidence interval [95% CI] 1.16, 6.85). Risk for ipsilateral SRE was unaffected by the presence of SRF among HRSFs (p = 0.561). Of low-risk patients with SRF, 33.3% experienced ipsilateral SRE, while those without SRF experienced no ipsilateral SRE (p 0.001).Endoscopically determined stone clearance predicts disease recurrence within 5 years after RIRS. Even SRF are an important risk factor for future stone-related (ipsilateral) events; therefore, patients with residual fragments of any size should not be labeled "stone free" and endoscopic stone treatment should aim at complete stone clearance.

Despite the significant impact of postoperative delirium on surgical outcomes and the long-term prognosis of older patients, its neural basis has not yet been clarified. In this study we investigated the impact of premorbid brain microstructural integrity, as measured by diffusion tensor imaging before surgery, on postoperative delirium incidence and severity, as well as the relationship among presurgical cognitive performance, diffusion tensor imaging abnormalities and postoperative delirium. Presurgical diffusion tensor imaging scans of 136 older (≥70 years), dementia-free subjects from the prospective Successful Aging after Elective Surgery study were analysed blind to the clinical data and delirium status. Primary outcomes were postoperative delirium incidence and severity during the hospital stay, as assessed by the Confusion Assessment Method. We measured cognition before surgery using general cognitive performance, a composite score based on a battery of neuropsychological tests. We investigated the association between presurgical diffusion tensor imaging parameters of brain microstructural integrity (i.e. fractional anisotropy, axial, mean and radial diffusivity) with postoperative delirium incidence and severity. Analyses were adjusted for the following potential confounders: age, gender, vascular comorbidity status, and general cognitive performance. Postoperative delirium occurred in 29 of 136 subjects (21%) during hospitalization. Presurgical diffusion tensor imaging abnormalities of the cerebellum, cingulum, corpus callosum, internal capsule, thalamus, basal forebrain, occipital, parietal and temporal lobes, including the hippocampus, were associated with delirium incidence and severity, after controlling for age, gender and vascular comorbidities. After further controlling for general cognitive performance, diffusion tensor imaging abnormalities of the cerebellum, hippocampus, thalamus and basal forebrain still remained associated with delirium incidence and severity. This study raises the intriguing possibility that structural dysconnectivity involving interhemispheric and fronto-thalamo-cerebellar networks, as well as microstructural changes of structures involved in limbic and memory functions predispose to delirium under the stress of surgery. While the diffusion tensor imaging abnormalities observed in the corpus callosum, cingulum, and temporal lobe likely constitute the neural substrate for the association between premorbid cognition, as measured by general cognitive performance, and postoperative delirium, the microstructural changes observed in the cerebellum, hippocampus, thalamus and basal forebrain seem to constitute a separate phenomenon that predisposes to postsurgical delirium independent of presurgical cognitive status.

To demonstrate the performance of a novel holmium laser enucleation technique in patients with lower urinary tract symptoms (LUTS). Between September 2015 and August 2017, 114 consecutive patients underwent modified HoLEP [3 horse shoe-like incision HoLEP (3 HSI HoLEP)] for LUTS performed by an experienced urologist (A.M.). The surgical intervention and short postoperative course were analyzed. International Prostate Symptom Score (IPSS), quality of life score, maximum urinary flow rate (Q max), postvoid residual urine (PVR), and clinical and sociodemographic data were assessed preoperatively. The patient cohort was compared with existing data regarding clinical outcome parameters after surgical LUTS therapy. The mean size of the prostatic gland was 86.3 ± 46.5 mL. The mean total operative time was 49.6 min (15–280 min). IPSS, Q max, and PVR were 20.7, 10.8, and 112.7 mL, respectively, prior to the intervention in the 3 HSI HoLEP group. The complication rate for Clavien category-III complications was 4.4%; no category IV complications were recorded. Seven of 114 patients experienced urinary retention after catheter removal during the hospital stay. The presented procedure provides several improvements over the standard modality. The prostatic gland is enucleated en bloc in an anatomical manner without longitudinal incisions of the urethra. This method is fast, safe, and may be easier to learn. However, this is the first description recorded. Future multicenter, controlled studies should clarify the long-term outcomes and surgical performance of 3 HSI HoLEP.

Intestinal anastomosis is a fundamental procedure in general surgery and required to restore intestinal continuity following resection. The aim of this study was to evaluate whether a gentamicin-coated polyvinylidene fluoride (PVDF) suture material has beneficial effect on anastomotic healing. Ninety Sprague-Dawley rats were divided into three groups: a PVDF-suture group, a gentamicin-coated PVDF (GPVDF)-suture group and a control group using Maxon® (polyglycolid-co-trimethylene carbonate). For each animal, a colonic anastomosis was performed. Ten animals from each group were sacrificed on postoperative days 3, 5, and 14. Measurements of anastomotic bursting pressure were performed on days 3 and 5. At each time, collagen type I/III ratio, MMP 2 and MMP-9 expression and the proliferation index (Ki67) were analyzed. In total, 90 animals underwent surgery without postoperative complications. Bursting strength in the GPVDF group was significantly elevated on day 5. Immunohistochemistry showed significant increase of the collagen type I/III ratio for PVDF and GPVDF on days 3 and 5. MMP2 was significantly increased for PVDF on days 3 and 5 and for GPVDF on day 5. The analysis of MMP9 revealed significant increase compared to control on day 3 and 5 (GPVDF) as well as on day 5 (PVDF). Staining for Ki67 revealed a significant elevation on postoperative day 3 for the PVDF and the GPVDF group. The present data shows the feasibility of PVDF as suture material for colonic anastomosis and confirms the ability of gentamicin to increase the stability of colonic anastomosis when used as coating material.

Background: Biocompatibility and tissue integration of a surgical suture are decisive factors for wound healing and therefore for the success of sutures. The optimal suture material is still under discussion. Polyvinylidene fluoride (PVDF) is described to have superior properties of biocompatibility and is therefore frequently used as a mesh component. Only little information is available about its use as a suture material. The aim of this study was to evaluate the biocompatibility of PVDF as a suture material in comparison to 5 different established sutures in a rat model. Methods: In 30 male rats, a monofilamental PVDF suture (Resopren®) and 5 established control suture materials [polyester (Miralene®), polytetrafluoroethylene (Gore®), poliglecaprone (Monocryl®), polydioxanone (Monoplus®), polyglactin 910 (Vicryl®), USP size 3-0] were placed in the subcutaneous layer of the abdominal wall without knot or tension. After 3, 7 or 21 days, the abdominal walls were explanted for histopathological and immunohistochemical investigation with special regard to the size and quality of foreign body granuloma and the length of the comet tail-like infiltrate (CTI). Results: The PVDF sutures showed the smallest size of foreign body granuloma (60 ± 14 µm) and the smallest CTI length (343 ± 60 µm) of all polymers after 21 days. Only PVDF (Resopren) and polydioxanone (Monoplus) showed a significant collagen I/III ratio increase between days 3 and 21 (p = 0.009 and p = 0.016). The quality of foreign body reaction regarding inflammation, proliferation and fibrotic remodeling was similar between all suture materials. Conclusions: Our data indicate that monofilamental PVDF sutures show a favorable foreign body reaction with small granuloma sizes and CTI length in comparison to established sutures. Its use as a suture material in general surgery could therefore be extended in the future. To reinforce these findings, further clinical studies need to be conducted.

Objective: To provide a comprehensive review of robot-assisted surgery in urolithiasis and to consider the future prospects of robotic approaches in stone surgery. Materials and methods: We performed a systematic PubMed© literature search using predefined Medical Subject Headings search terms to identify PubMed-listed clinical research studies on robotic stone surgery. All authors screened the results for eligibility and two independent reviewers performed the data extraction. Results: The most common approach in robotic stone surgery is a robot-assisted pyelolithotomy using the da Vinci™ system (Intuitive Surgical Inc., Sunnyvale, CA, USA). Several studies show this technique to be comparable to classic laparoscopic and open surgical interventions. One study that focused on ureteric stones showed a similar result. In recent years, promising data on robotic intrarenal surgery have been reported (Roboflex Avicenna™; Elmed Medical Systems, Ankara, Turkey). Initial studies have shown its feasibility and high stone-free rates and prove that this novel endoscopic approach is safe for the patient and comfortable for the surgeon. Conclusions: The benefits of robotic devices in stone surgery in existing endourological, laparoscopic, and open treatment strategies still need elucidation. Although recent data are promising, more prospective randomised controlled studies are necessary to clarify the impact of this technique on patient safety and stone-free rates. Keywords: Robotic stone surgery, Urolithiasis, Nephrolithiasis, Stone disease, Endourology

White matter hyperintensities (WMHs) and lacunes are magnetic resonance imaging hallmarks of cerebral small-vessel disease, which increase the risk of stroke, cognitive, and mobility impairment. Although most studies of cerebral small-vessel disease have focused on white matter abnormalities, the gray matter (GM) is also affected, as evidenced by frequently observed lacunes in subcortical GM. Diffusion tensor imaging (DTI) is sensitive to subtle neurodegenerative changes in deep GM structures. We explored the relationship between baseline DTI characteristics of the thalamus, caudate, and putamen, and the volume and subsequent accrual of WMHs over a 4-year period in 56 community-dwelling older (≤75 years) individuals. Baseline thalamic fractional anisotropy (FA) was an independent predictor of WMH accrual. WMH accrual also correlated with baseline lacune count and baseline WMH volume, the latter showing the strongest predictive power, explaining 27.3% of the variance. The addition of baseline thalamic FA in multivariate modeling increased this value by 70%, which explains 46.5% of the variance in WMH accrual rate. Thalamic FA might serve as a novel predictor of cerebral small-vessel disease progression in clinical settings and trials. Furthermore, our findings point to the possibility of a causal relationship between thalamic damage and the accrual of WMHs.