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PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

STUDY DESIGN Retrospective review. OBJECTIVE The aim of this study was to understand the potential correlation of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey response time on reported satisfaction following spine surgery hospitalization. SUMMARY OF BACKGROUND DATA With increasing emphasis on patient satisfaction metrics, such as HCAHPS, hospital reputations, and reimbursements are being affected by the results of such surveys. HCAHPS is a 32-question survey about patient experience in the hospital and after discharge. METHODS HCAHPS surveys were routinely sent to all patients admitted after spine surgery at an academic medical center between January 2013 and August 2017. Survey data, survey return time, patient demographics, and 30-day postoperative outcomes were gathered for all spine surgery patients who returned the survey. Multivariate regression analysis controlling for age, sex, BMI, functional status, American Society of Anesthesiologists class, education, and race was used to determine whether there were differences in rates of "Top Box" response between different time ranges of survey return. RESULTS In total, 1495 consecutive spinal surgery patients who returned their HCAHPS survey were identified. Of these, 31.51% returned their surveys within 21 days, 48.09% returned them between 22 to 42 days, 13.58% returned them between 43 to 64 days, and 6.82% returned them ≥65 days after distribution. Multivariate regression demonstrated no statistical differences in reported satisfaction between surveys returned between days 0 to 21 and days 22 to 42. However, there were significantly lower scores reported by surveys returned on days 43 to 64 and 65 plus days. CONCLUSION Centers for Medicare and Medicaid Services only considers HCAHPS surveys returned within the first 42 days. It appears that the survey responses are similar over this time period. Beyond this time, lower scores are reported. Further attention to this less satisfied, later HCAHPS survey returning group seems warranted.Level of Evidence: 2.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

Background Research experience is believed to be an important component of the neurosurgery residency application process. One measure of research productivity is publication volume. The preresidency publication volume of U.S. neurosurgery interns and any potential association between applicant publication volume and the match results of top-ranked residency programs have not been well characterized. Objective In this study, we sought to characterize the preresidency publication volume of U.S. neurosurgery residents in the 2018–2019 intern class using the Scopus database. Methods For each intern, we recorded the total number of publications, total number of first or last author publications, total number of neuroscience-related publications, mean number of citations per publication, and mean impact factor of the journal per publication. Preresidency publication volumes of interns at the top-25 programs (based on a composite ranking score according to 4 different ranking metrics) were compared with those at all other programs. Results We found that 82% of neurosurgery interns included in the analysis (190 interns from 95 programs) had at least 1 publication. The average number of publications per intern among all programs was 6 ± 0.63 (mean ± standard error of the mean). We also found that interns at top-25 neurosurgery residency programs tended to have a higher number of publications (8.3 ± 1.2 vs. 4.8 ± 0.7, P = 0.0137), number of neuroscience-related publications (6.8 ± 1.1 vs. 4.1 ± 0.7, P = 0.0419), and mean number of citations per publication (9.8 ± 1.7 vs. 5.7 ± 0.8, P = 0.0267) compared with interns at all other programs. Conclusions Our results provide a general estimate of the preresidency publication volume of U.S. neurosurgery interns and suggest a potential association between publication volume and matching in the top-25 neurosurgery residency programs.

Hydrocephalus is the most common neurosurgical disorder worldwide and is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles resulting from failed CSF homeostasis. Since the 1840s, physicians have observed inflammation in the brain and the CSF spaces in both posthaemorrhagic hydrocephalus (PHH) and postinfectious hydrocephalus (PIH). Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells and physical irritants; however, inappropriately triggered or sustained inflammation can respectively initiate or propagate disease. Recent data have begun to uncover the molecular mechanisms by which inflammation - driven by Toll-like receptor 4-regulated cytokines, immune cells and signalling pathways - contributes to the pathogenesis of hydrocephalus. We propose that therapeutic approaches that target inflammatory mediators in both PHH and PIH could address the multiple drivers of disease, including choroid plexus CSF hypersecretion, ependymal denudation, and damage and scarring of intraventricular and parenchymal (glia-lymphatic) CSF pathways. Here, we review the evidence for a prominent role of inflammation in the pathogenic mechanism of PHH and PIH and highlight promising targets for therapeutic intervention. Focusing research efforts on inflammation could shift our view of hydrocephalus from that of a lifelong neurosurgical disorder to that of a preventable neuroinflammatory condition.

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

Dilation of the fluid-filled cerebral ventricles (ventriculomegaly) characterizes hydrocephalus and is frequently seen in autism and schizophrenia. Recent work suggests that the genomic study of congenital hydrocephalus may be unexpectedly fertile ground for revealing insights into neural stem cell regulation, human cerebrocortical development, and pathogenesis of neuropsychiatric disease.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to similar to 22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

A 3-year-old girl presented with progressive macrocephaly and a history of open myelomeningocele surgically repaired at birth. She had no history of intracranial hemorrhage or meningitis. Physical examination showed head circumference >99th percentile (54 cm) and decreased lower extremity motor function. Neuroimaging revealed extreme communicating ventriculomegaly and strikingly turbulent intraventricular CSF flow in the setting of diffuse cortical atrophy (figure, A–C). A ventriculoperitoneal shunt was placed. Intraoperatively, her intracranial pressure was 18 cm CSF (13.2 mm Hg) (normal in children: 3–7 mm Hg). Postoperative imaging showed complete resolution of intraventricular CSF turbulence with a mild decrease in ventriculomegaly (figure, D–F). The patient continued to exhibit mild neurocognitive impairments with arrest of progressive macrocephaly.

Importance Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, setting, and participants A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main outcomes and measures Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and relevance These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.

Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells, and physical irritants. However, inappropriately triggered or sustained inflammation can respectively initiate, propagate, or prolong disease. Post-hemorrhagic (PHH) and post-infectious hydrocephalus (PIH) are the most common forms of hydrocephalus worldwide. They are treated using neurosurgical cerebrospinal fluid (CSF) diversion techniques with high complication and failure rates. Despite their distinct etiologies, clinical studies in human patients have shown PHH and PIH share similar CSF cytokine and immune cell profiles. Here, in light of recent work in model systems, we discuss the concept of "inflammatory hydrocephalus" to emphasize potential shared mechanisms and potential therapeutic vulnerabilities of these disorders. We propose that this change of emphasis could shift our thinking of PHH and PIH from a framework of life-long neurosurgical disorders to that of preventable conditions amenable to immunomodulation.

The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and pre-clinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of pathological cerebrospinal fluid (CSF) accumulation and, therefore, treated largely by neurosurgical CSF diversion. The persistence of ventriculomegaly and poor neurodevelopmental outcomes in some post-surgical patients highlights our limited knowledge of disease mechanisms. Recent whole-exome sequencing (WES) studies have shown that rare, damaging de novo and inherited mutations with large effect contribute to ~ 25% of sporadic CH. Interestingly, multiple CH genes are key regulators of neural stem cell growth and differentiation and converge in human transcriptional networks and cell types pertinent to fetal neurogliogenesis. These data implicate genetic disruption of early brain development as the primary pathomechanism in a substantial minority of patients with sporadic CH, shedding new light on human brain development and the pathogenesis of hydrocephalus. These data further suggest WES as a clinical tool with potential to re-classify CH according to a molecular nomenclature of increased precision and utility for genetic counseling, outcome prognostication, and treatment stratification.

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI). Methods: Preprocessed 18F-AV-1451 tau and 18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. Results: After applying PVC and controlling for age, education level and global cortical 18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. Conclusions: Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.

Acetylserotonin O-methyltransferase (ASMT) is a key enzyme in the synthesis of melatonin. Although melatonin has been shown to exhibit anticancer activity and prevents endocrine resistance in breast cancer, the role of ASMT in breast cancer progression remains unclear. In this retrospective study, we analyzed gene expression profiles in 27 data sets on 7244 patients from 11 countries. We found that ASMT expression was significantly reduced in breast cancer tumors relative to healthy tissue. Among breast cancer patients, those with higher levels of ASMT expression had better relapse-free survival outcomes and longer metastasis-free survival times. Following treatment with tamoxifen, patients with greater ASMT expression experienced longer periods before relapse or distance recurrence. Motivated by these results, we devised an ASMT gene signature that can correctly identify low-risk cases with a sensitivity and specificity of 0.997 and 0.916, respectively. This signature was robustly validated using 23 independent breast cancer mRNA array data sets from different platforms (consisting of 5800 patients) and an RNAseq data set from TCGA (comprising 1096 patients). Intriguingly, patients who are classified as high-risk by the signature benefit from adjuvant chemotherapy, and those with grade II tumors who are classified as low-risk exhibit improved overall survival and distance relapse-free outcomes following endocrine therapy. Together, our findings more clearly elucidate the roles of ASMT, provide strategies for improving the efficacy of tamoxifen treatment and help to identify those patients who may maximally benefit from adjuvant or endocrine therapies.

Spinal cord stimulation (SCS) has been considered as an alternative therapy to reduce opioid requirements in certain chronic pain disorders. However, information on long-term opioid consumption patterns and their impact on SCS device explantation is lacking. We conducted a retrospective study of 45 patients to characterize long-term patterns of opioid usage after SCS implantation. Daily morphine equivalent dosage (MED) increased, decreased, and remained the same in 40%, 40%, and 20% of patients at 1-year follow-up, respectively. Twelve (27%) underwent explantation due to treatment failure at a median of 18 months after implantation. Pre-operative opioid status (naive vs. active use) was not associated with explantation (18% vs. 29%, p = 0.699) and neither was the daily MED change status (i.e. increased, decreased, unchanged) at 1-year (p = 0.499, 1.000, 0.735, respectively). Following explantation, reduction in the daily MED was seen in 92% of patients with dosages falling below pre-operative baseline in nine. Among the opioid naive patients, 55% were on opioids at last follow-up (average 32.4 ± 14.6 months). Our results indicate that daily opioid consumption does not decrease in most patients 1-year after SCS implantation. Furthermore, post-operative evaluation beyond 1-year is necessary to assess the efficacy and durability of SCS therapy as well as its impact on opioid requirement. Lastly, rigorous patient selection and pre-operative risk assessment for misuse and dependence are paramount to improving outcome after SCS implantation.

INTRODUCTION: Epilepsy is a common neurological disorder of neuronal hyperexcitability that begets recurrent and unprovoked seizures. The lack of a truly satisfactory pharmacotherapy for epilepsy highlights the clinical urgency for the discovery of new drug targets. To that end, targeting the electroneutral K(+)/Cl(−) cotransporter KCC2 has emerged as a novel therapeutic strategy for the treatment of epilepsy. AREAS COVERED: We summarize the roles of KCC2 in the maintenance of synaptic inhibition and the evidence linking KCC2 dysfunction to epileptogenesis. We also discuss preclinical proof-of-principle studies that demonstrate that augmentation of KCC2 function can reduce seizure activity. Moreover, potential strategies to modulate KCC2 activity for therapeutic benefit are highlighted. EXPERT OPINION: Although KCC2 is a promising drug target, questions remain before clinical translation. It is unclear whether increasing KCC2 activity can reverse epileptogenesis, the ultimate curative goal for epilepsy therapy that extends beyond seizure reduction. Furthermore, the potential adverse effects associated with increased KCC2 function have not been studied. Continued investigations into the neurobiology of KCC2 will help to translate promising preclinical insights into viable therapeutic avenues that leverage fundamental properties of KCC2 to treat medically intractable epilepsy and other disorders of failed synaptic inhibition with attendant neuronal hyperexcitability.

Psychotropic medications have modulatory effects on spinal cord stimulator (SCS) therapy and may play an important role in determining treatment success in chronic pain management. However, it remains unknown how SCS affects psychotropic use and whether the medications affect outcome. We performed a retrospective study to determine the prevalence of psychotropic medication (i.e. anxiolytic, antidepressant, and anticonvulsant) use among new SCS patients immediately before implantation and characterized the dosage changes at 1-year. We also sought to understand whether pre-operative medication status affects outcome, defined as device explantation due to treatment failure. In an analysis of 45 patients, 31%, 51% and 71% were actively taking anxiolytics, antidepressants, and anticonvulsants, respectively, before surgery. In the majority of cases, daily dosages remained the same for all three classes of medication at 1-year. Patients who were on two or more classes of medications pre-operatively had significantly lower explantation rate compared to those with one or none (12% vs. 43%, p = 0.041) and had 5.25 times less likelihood of explanation in the future (OR 5.25, 95%CI 1.18–23.2, p = 0.029). Our study suggest that peri-operative multimodality medical treatment may enhance the therapeutic efficacy and durability of SCS in carefully selected chronic pain patients.

BREAST-Q is a validated measure of patient satisfaction and health-related quality of life following breast surgery. Limited evidence exists with regard to the influence of preoperative overall health status on BREAST-Q outcomes. The American Society of Anesthesiologists (ASA) physical status classification is representative of preoperative overall health and its impact on patient-reported outcomes can be assessed.Patients who received breast reconstruction at Yale New Haven Hospital between 2013 and 2018 and completed the BREAST-Q were enrolled in the study. Associations between BREAST-Q scores within modules and between modules and ASA were analyzed. Pearson's correlation and Spearman's Rho were used to characterize correlations between patient factors and BREAST-Q scores. Significantly correlated factors were entered into a general linear model (GLM) to control for confounding variables and isolate the effect of ASA on BREAST-Q scores.A total of 1136 patients underwent breast reconstruction of whom 489 patients completed the BREAST-Q. Increasing ASA indicative of worsening overall health was associated with a decreased BREAST-Q score for all modules except Physical Well-being of the Abdomen (p0.01 to p = 0.029). In a GLM controlling for relevant covariates, ASA remained a significant contributor for all modules except Physical Well-being of the Chest (p0.01 to p = 0.021). BREAST-Q scores decreased by approximately twice as much from ASA 1 to 2 compared to ASA 2 to 3.ASA classification is an independent predictor of BREAST-Q patient-reported outcomes following breast reconstruction. Communicating the potential impact of overall health may help reduce the discrepancy in postoperative satisfaction across ASA classifications.

Tripartite motif 71 (Trim71)/lineage defective 41 (lin-41) is the primary target of the ancient lethal 7 (let-7) miRNA that is essential for survival and development across animal phylogeny. Recent work identified Trim71 as a critical regulator of mammalian neural stem cell (NSC) fate and a bona fide human disease gene in congenital hydrocephalus (CH). Studying TRIM71 as a paradigm of NSC involvement in CH is a remarkable opportunity to better understand the mechanisms that regulate the timing of brain development and the pathogenesis of the most common pediatric neurosurgical disorder.

We performed a retrospective study to characterize the timing and prevalence of revision and removal surgeries after spinal cord stimulator (SCS) implantation in patients with chronic pain. In our analysis of 100 patients who had SCS implants, we found that 34% of patients underwent revision surgery and 53% of patients had their implant removed. Of the patients who required revision surgeries, the majority (56%) eventually opted for removal of their SCS system. The median time to the first revision surgery was 16 months post implantation and the median time to removal was 39 months post implantation. Our findings demonstrate that most SCS systems are removed within a few years post implantation, highlighting the clinical need for a more complete understanding of SCS technology in order to refine patient selection criteria.

This study evaluates whole-exome sequencing as a diagnostic tool in a cohort of neurosurgically treated congenital hydrocephalus probands.

ObjectiveMultiple clinical trials fail to identify clinically measurable health benefits of daily multivitamin and multimineral (MVM) consumption in the general adult population. Understanding the determinants of widespread use of MVMs may guide efforts to better educate the public about effective nutritional practices. The objective of this study was to compare self-reported and clinically measurable health outcomes among MVM users and non-users in a large, nationally representative adult civilian non-institutionalised population in the USA surveyed on the use of complementary health practices.DesignCross-sectional analysis of the effect of MVM consumption on self-reported overall health and clinically measurable health outcomes.ParticipantsAdult MVM users and non-users from the 2012 National Health Interview Survey (n=21 603).Primary and secondary outcome measuresFive psychological, physical, and functional health outcomes: (1) self-rated health status, (2) needing help with routine needs, (3) history of 10 chronic diseases, (4) presence of 19 health conditions in the past 12 months, and (5) Kessler 6-Item (K6) Psychological Distress Scale to measure non-specific psychological distress in the past month.ResultsAmong 4933 adult MVM users and 16 670 adult non-users, MVM users self-reported 30% better overall health than non-users (adjusted OR 1.31; 95% CI 1.17 to 1.46; false discovery rate adjusted pConclusionsMVM users self-reported better overall health despite no apparent differences in clinically measurable health outcomes. These results suggest that widespread use of multivitamins in adults may be a result of individuals’ positive expectation that multivitamin use leads to better health outcomes or a self-selection bias in which MVM users intrinsically harbour more positive views regarding their health.

The goal of this study was to identify a strategy for antiepileptic drug (AED) reduction to allow efficient recording of focal seizures (FS) in patients undergoing video-electroencephalography (EEG) in an epilepsy monitoring unit (EMU) while avoiding the risk of complications associated with more severe seizure types.We retrospectively reviewed consecutive patients admitted to our institution's EMU from July 1, 2016 to December 31, 2017. We included 114 presurgical patients who had AEDs reduced and at least one seizure during the admission. We compared AED dosages at which FS versus focal to bilateral tonic-clonic seizures (f-BTCS), seizure clusters, and lorazepam administration occurred. We also examined rate of AED reduction and seizure types. We used a receiver-operating characteristic (ROC) curve to identify a dose maximizing FS and minimizing other seizure types.Antiepileptic drug withdrawal rates ranged from 0 to 100% in the first 24 h (mean: 20%, standard deviation: 20%). Focal to bilateral tonic-clonic seizures and lorazepam administration occurred at a lower median AED dose than did FS (0%, 7.2%, and 43.8%, respectively, expressed as a percentage of the patient's outpatient daily AED dose; p 0.001). A daily EMU-administered dose of one-third of the patient's outpatient AED dose allowed 55.0% of FS to occur while avoiding 82.0% of more severe seizure types. The seizure types had no difference in rate of AED withdrawal in the first 24 h of EMU stay.Focal seizures occurred at a higher AED dose than did f-BTCS. This may imply that a low minimally effective dose of AED could allow FS to be recorded while providing protection against f-BTCS. This strategy could improve efficacy and safety in the EMU.

Failed back surgery syndrome (FBBS) is characterized by chronic pain that persists following spine surgery. In this review, we discuss the use of spinal cord stimulation (SCS) for FBBS treatment and how the clinical use of SCS may be influenced by private manufacturers. While SCS therapy can be promising for the appropriate patient, there remain knowledge gaps in understanding the full potential of SCS technology for delivering optimal therapeutic benefit. We caution that the use of SCS without a complete understanding of the technology may create exploitative situations that private manufacturers can capitalize on while subjecting patients to potentially unnecessary health and financial burdens.

Summary This study quantifies the spatio-temporal association between outbreaks of highly pathogenic avian influenza H5N1 in domestic poultry (n = 3050) and human cases (n = 99) in Vietnam during 2003–2007, using rare events logisitic regression. After adjusting for the effect of known confounders, the odds of a human case being reported to authorities increased by a factor of 6.17 [95% confidence interval (CI) 3.33–11.38] and 2.48 (95% CI 1.20 – 5.13) if poultry outbreaks were reported in the same district 1 week and 4 weeks later respectively. When jointly considering poultry outbreaks in the same and neighbouring districts, occurrence of poultry outbreaks in the same week, 1-week later, and 4 weeks later increased the odds of a human case by a factor of 2.75 (95% CI 1.43–5.30), 2.56 (95% CI 1.31–5.00) and 2.70 (95% CI 1.56–4.66) respectively. Our study found evidence of different levels of association between human cases and poultry outbreaks in the North and the South of the country. When considering the 9-week interval extending from 4 weeks before to 4 weeks after the week of reporting a human case, in the South poultry outbreaks were recorded in 58% of cases in the same district and 83% of cases in either the same or neighbouring districts, whereas in the North the equivalent results were only 23% and 42%. The strength of the association between human and poultry cases declined over the study period. We conclude that owner reporting of clinical disease in poultry needs to be enhanced by targeted agent-specific surveillance integrated with preventive and other measures, if human exposure is to be minimized.

Low levels of the survival motor neuron protein (SMN) cause the disease spinal muscular atrophy. A primary characteristic of this disease is motoneuron dysfunction and paralysis. Understanding why motoneurons are affected by low levels of SMN will lend insight into this disease and to motoneuron biology in general. Motoneurons in zebrafish smn mutants develop abnormally; however, it is unclear where Smn is needed for motoneuron development since it is a ubiquitously expressed protein. We have addressed this issue by expressing human SMN in motoneurons in zebrafish maternal-zygotic (mz) smn mutants. First, we demonstrate that SMN is present in axons, but only during the period of robust motor axon outgrowth. We also conclusively demonstrate that SMN acts cell autonomously in motoneurons for proper motoneuron development. This includes the formation of both axonal and dendritic branches. Analysis of the peripheral nervous system revealed that Schwann cells and dorsal root ganglia (DRG) neurons developed abnormally in mz-smn mutants. Schwann cells did not wrap axons tightly and had expanded nodes of Ranvier. The majority of DRG neurons had abnormally short peripheral axons and later many of them failed to divide and died. Expressing SMN just in motoneurons rescued both of these cell types showing that their failure to develop was secondary to the developmental defects in motoneurons. Driving SMN just in motoneurons did not increase survival of the animal, suggesting that SMN is needed for motoneuron development and motor circuitry, but that SMN in other cells types factors into survival.

SummaryMicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. In order to identify miRNAs and to assess their expression patterns, we sequenced over 250 small RNA libraries from 26 different organ systems and cell types of human and rodents that were enriched in neuronal as well as normal and malignant hematopoietic cells and tissues. We present expression profiles derived from clone count data and provide computational tools for their analysis. Unexpectedly, a relatively small set of miRNAs, many of which are ubiquitously expressed, account for most of the differences in miRNA profiles between cell lineages and tissues. This broad survey also provides detailed and accurate information about mature sequences, precursors, genome locations, maturation processes, inferred transcriptional units, and conservation patterns. We also propose a subclassification scheme for miRNAs for assisting future experimental and computational functional analyses.