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In this study we aimed to identify the molecular genetic cause of a progressive multisystem disease with prominent lipodystrophy.In total, 5 affected individuals were investigated using exome sequencing. Dermal fibroblasts were characterized using RNA sequencing, proteomics, immunoblotting, immunostaining, and electron microscopy. Subcellular localization and rescue studies were performed.We identified a lipodystrophy phenotype with a typical facial appearance, corneal clouding, achalasia, progressive hearing loss, and variable severity. Although 3 individuals showed stunted growth, intellectual disability, and died within the first decade of life (A1, A2, and A3), 2 are adults with normal intellectual development (A4 and A5). All individuals harbored an identical homozygous nonsense variant affecting the retention and splicing complex component BUD13. The nucleotide substitution caused alternative splicing of BUD13 leading to a stable truncated protein whose expression positively correlated with disease expression and life expectancy. In dermal fibroblasts, we found elevated intron retention, a global reduction of spliceosomal proteins, and nuclei with multiple invaginations, which were more pronounced in A1, A2, and A3. Overexpression of both BUD13 isoforms normalized the nuclear morphology.Our results define a hitherto unknown syndrome and show that the alternative splice product converts a loss-of-function into a hypomorphic allele, thereby probably determining the severity of the disease and the survival of affected individuals.

Clinical validity assessments of gene-disease associations underpin analysis and reporting in diagnostic genomics, and yet wide variability exists in practice, particularly in use of these assessments for virtual gene panel design and maintenance. Harmonization efforts are hampered by the lack of agreed terminology, agreed gene curation standards, and platforms that can be used to identify and resolve discrepancies at scale. We undertook a systematic comparison of the content of 80 virtual gene panels used in two healthcare systems by multiple diagnostic providers in the United Kingdom and Australia. The process was enabled by a shared curation platform, PanelApp, and resulted in the identification and review of 2,144 discordant gene ratings, demonstrating the utility of sharing structured gene-disease validity assessments and collaborative discordance resolution in establishing national and international consensus.

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer's disease. We tested whether functional connectivity (FC) within the entorhinal–hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-β (Aβ) pathology in a sample of 64 cognitively normal human older adults (mean age, 71.3 ± 6.4 years; 67% female). FC was measured between entorhinal–hippocampal circuit nodes with known anatomical connectivity, as well as within cortical memory networks. Aβ pathology was measured with18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low-performing and high-performing groups on each task using a median split. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC and DG/CA3 was related to Aβ pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. Aβ was further associated with dysfunction within hippocampal subfields, particularly with decreased FC between CA1 and subiculum as well as reduced volume in these regions. Our findings suggest that Aβ may indirectly lead to memory impairment through entorhinal–hippocampal circuit dysfunction and neurodegeneration and provide a mechanism for increased vulnerability of object mnemonic discrimination.SIGNIFICANCE STATEMENTMnemonic discrimination is a critical episodic memory process that is performed in the dentate gyrus (DG) and CA3 subfield of the hippocampus, relying on input from entorhinal cortex. Mnemonic discrimination is particularly vulnerable to decline in older adults; however, the mechanisms behind this vulnerability are still unknown. We demonstrate that object mnemonic discrimination impairment is related to hyperconnectivity between the anterolateral entorhinal cortex and DG/CA3. This hyperconnectivity was associated with amyloid-β pathology and neurodegeneration in entorhinal cortex, suggesting aberrantly increased network activity is a pathological process. Our findings provide a mechanistic explanation of the vulnerability of object compared to spatial mnemonic discrimination in older adults and has translational implications for choice of outcome measures in clinical trials for Alzheimer's disease.

Background Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data. Methods Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon–intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon–intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. Results We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. Conclusions Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases.

Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

Objective The aims of this study were to: (1) characterize the menopause transition (MT) on social media and (2) determine if concordance or discordance exists when comparing MT-focused social media posts and biomedical research literature. Methods We analyzed 440 sequential Instagram posts with the hashtag #menopause over 2 weeks from January to February 2019. Posts were composed of 299 unique accounts, resulting in an average of 1.7 posts per account (standard deviation [SD] 1; range 1-9; median 1 and interquartile range [IQR] 1-2). Each account had an average of 2,616 followers (SD 11,271; range 3-129,000; median 421.5 and IQR 177-1,101). Content and thematic analyses were completed for posts, images, and videos to identify codes related to the MT. The top 15 codes were then searched along with the key term "menopause" in PubMed to ascertain the level of concordance between Instagram content and peer-reviewed literature on the MT. Results We identified 69 codes in our corpus of Instagram content, resulting in 9 categories: physical health, mental health, complementary and integrative health, advertising, social, advice, self-care, nature, and self-expression (kappa 0.95-1.00). The most prevalent codes were related to weight loss/fitness (20.5%) and hormones (18.4%). The majority of frequent codes identified in Instagram posts were infrequently listed in biomedical literature related to menopause. However, there were two codes, Weight loss/Fitness and Hot flashes, that were frequently discussed in Instagram posts and the biomedical literature. Conclusions The examination of #menopause on Instagram provides novel insights for researchers and clinicians. Our findings provide a better understanding of the experiences and support needs of individuals experiencing menopause. Furthermore, codes related to menopause have low prominence in the biomedical literature, suggesting key topics that could be explored in the future.

BACKGROUND: Repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders.METHODS: We retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013-17 to the 100 000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result.FINDINGS: The diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2-99·0) and 99·6% specificity (99·1-99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11 631 patients in the 100 000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate).INTERPRETATION: In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder.FUNDING: Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina.

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders., Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

Background A crisis in pain management persists, as does the epidemic of opioid overdose deaths, addiction, and diversion. Pain medicine is meeting these challenges by returning to its origins: the Bonica model of multidisciplinary pain care. The 2018 Academic Consortium White Paper detailed the historical context and magnitude of the pain crisis and the evidence base for nonpharmacologic strategies. More than 50% of chronic opioid use begins in the acute pain care setting. Acupuncture may be able to reduce this risk. Objective This article updates the evidence base for acupuncture therapy for acute pain with a review of systematic reviews and meta-analyses on postsurgical/perioperative pain with opioid sparing and acute nonsurgical/trauma pain, including acute pain in the emergency department. Methods To update reviews cited in the 2018 White Paper, electronic searches were conducted in PubMed, MEDLINE, CINAHL, and the Cochrane Central Register of Controlled Trials for “acupuncture” and “acupuncture therapy” and “acute pain,” “surgery,” “peri-operative,” “trauma,” “emergency department,” “urgent care,” “review(s) ,” “systematic review,” “meta-analysis,” with additional manual review of titles, links, and reference lists. Results There are 22 systematic reviews, 17 with meta-analyses of acupuncture in acute pain settings, and a review for acute pain in the intensive care unit. There are additional studies of acupuncture in acute pain settings. Conclusion The majority of reviews found acupuncture therapy to be an efficacious strategy for acute pain, with potential to avoid or reduce opioid reliance. Future multicenter trials are needed to clarify the dosage and generalizability of acupuncture for acute pain in the emergency department. With an extremely low risk profile, acupuncture therapy is an important strategy in comprehensive acute pain care.

OBJECTIVE The purpose of this study was to test the association of two dimensions of self-awareness with hot flash (HF) severity. METHODS A subset of women from the Seattle Midlife Women's Health Study (N = 232) provided data for these analyses. Structural equation modeling was used to evaluate two dimensions of self-awareness (Internal States Awareness [ISA] and Self-Reflectiveness [SR]), and secondary factors of perceived stress, anxiety, and attitudes toward menopause as continuous with earlier life, health perceptions, and menopausal stage with respect to HF severity. The measurement and structural models were tested with a maximum likelihood missing values estimator and displayed good model fit. RESULTS Women with greater ISA reported greater HF severity (β = 0.17, P

PurposeGenome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease.MethodsGS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP.ResultsSixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%), and copy-number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%).ConclusionGS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximize the potential of clinical GS.

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia., The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases. ispartof: ARTHRITIS & RHEUMATOLOGY vol:73 issue:6 pages:1073-1085 ispartof: location:United States status: published

Congenital cranial dysinnervation disorders (CCDDs) are a heterogeneous group of neurodevelopmental phenotypes caused by a primary disturbance of innervation due to deficient, absent, or misguided cranial nerves. Although some CCDDs genes are known, several clinical phenotypes and their aetiologies remain to be elucidated. We describe a 12-year-old boy with hypotonia, developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. He had a long expressionless face, severe oromotor dysfunction, bilateral agenesis/severe hypoplasia of the VIII nerve with marked atresia of the internal auditory canals and cochlear labyrinth malformation. Trio-exome sequencing identified a homozygous loss of function variant in the NEUROG1 gene (NM_006161.2: c.202G > T, p.Glu68*). NEUROG1 is considered a causal candidate for CCDDs based on (i) the previous report of a patient with a homozygous gene deletion and developmental delay, deafness due to absent bilateral VIII nerves, and severe oromotor dysfunction; (ii) a second patient with a homozygous NEUROG1 missense variant and corneal opacity, absent corneal reflex and intellectual disability; and (iii) the knockout mouse model phenotype which highly resembles the disorder observed in humans. Our findings support the growing compelling evidence that loss of NEUROG1 leads to a very distinctive disorder of cranial nerves development. info:eu-repo/semantics/publishedVersion

Background Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting. Objective The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS. Methods A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models. Results A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25–0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88–0.99), higher serum IgA (OR 0.37, 95% CI 0.17–0.80) and higher serum IgG (OR 0.81, 95% CI 0.67–0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75–0.96) and higher serum IgA (OR 0.23, 95% CI 0.07–0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06–1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02–3.86) were associated with increased odds of antimicrobial use. Conclusions Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00810-3.

The coronavirus disease 2019 (COVID-19) pandemic has precipitated expansion of telemedicine in outpatient management of chronic diseases including multiple sclerosis (MS). Studies conducted pre-pandemic, when telehealth was an alternative to in-person consultations, represent a different setting to current practice. The aim of this study was to assess the impact of telehealth on MS outpatient care in a tertiary metropolitan hospital in Melbourne, Australia during the COVID-19 pandemic.From March-December 2020, patients and clinicians in the MS outpatient clinic were surveyed regarding their attitudes towards telehealth. Scores on the Expanded Disability Status Scale (EDSS) from telehealth and face-to-face appointments during the study period were compared to scores from face-to-face consultations before and after this period. Medical records were reviewed to compare management decisions made during telehealth versus face-to-face consultations. Diagnoses and treatment of MS relapses were compared to 2019.Telehealth was used in 73% of outpatient appointments. Patient satisfaction was generally high. Patients and clinicians preferred face-to-face consultations but were willing to use telehealth longer term. Overall, there were no significant delays in identifying patients experiencing disability worsening via telehealth, but EDSS increase was recorded in more face-to-face than telehealth appointments particularly for those with lower baseline disability. Disease-modifying therapy commencement rates were similar, but symptomatic therapy initiation and investigation requests occurred more frequently in face-to-face visits. Comparable numbers of MS relapses were diagnosed and treated with corticosteroids in 2019 and 2020.Patient satisfaction with telehealth was high, but both clinicians and patients preferred in-person appointments. Telehealth implementation did not lead to high rates of undetected disability worsening or undiagnosed acute relapses, but telehealth-based EDSS assessment may underestimate lower scores. Treatment inertia may affect some management decisions during telehealth consultations. Telehealth will likely play a role in outpatient settings beyond the COVID-19 pandemic with further studies on its long-term impact on clinical outcomes required.

Objective To elicit novel ideas for informatics solutions to support individuals through the menopausal transition. (Note: We use “individuals experiencing menopause” and “experiences” rather than “symptoms” when possible to counter typical framing of menopause as a cisgender women’s medical problem.) Methods A participatory design study was conducted 2015–2017 in the Western US. Two sessions were held with individuals experiencing menopause recruited from the general public; and 3 sessions with healthcare practitioners (HCPs) including nurses, physicians, and complementary and integrative health (CIH) practitioners were held. Participants designed technologies addressing informational needs and burdensome experiences. HCPs reflected on designs from participants experiencing menopause. Directed content analysis was used to analyze transcripts. Results Eight individuals experiencing menopause (n = 4 each session) and 18 HCPs (n = 10 CIH, n = 3 nurses, n = 5 physicians) participated. All participants provided ideas for solution purpose, hardware, software, features and functions, and data types. Individuals experiencing menopause designed technologies to help understand and prevent burdensome menopause experiences. HCPs designed technologies for tracking and facilitating communication. Compared to nurses and physicians, CIH practitioners suggested designs reframing menopause as a positive experience and accounted for the complex lives of individuals experiencing menopause, including stigma; these ideas corresponded to comments made by participants experiencing menopause. Participants from both populations were concerned about data confidentiality and technology accessibility. Conclusions Participant generated design ideas included novel ideas and incorporated existing technologies. This study can inform the development of new technologies or repurposing of existing technologies to support individuals through the menopausal transition.

Highlights • Covid-19 pandemic can have implications for MS and neuroimmunology patients and potentially their adherence to disease modifying therapies (DMTs). • A large proportion of patients receiving DMT's for their MS expressed some degree of concern regarding the COVID-19 pandemic and their therapy in one MS centre in Australia. • The level of concern in most patients was at most mild however. • Patients ascribed similar concern to the risk of a relapse of their disease compared to the risk of contracting COVID-19, perhaps underscoring a willingness to continue their DMT despite the pandemic., Objective: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19. This concept can pose a degree of anxiety for patients as well as neurologists. We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic. Methods: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making. Results: 170 patients completed the survey. Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern. Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups. Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern. More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making. Conclusions: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical risk for more severe disease, the overall level of concern in most cases was at most mild. Patients on B-cell depleting therapies were more inclined to express a higher level of concern. A similar concern was ascribed to a risk of a relapse or worsening MS symptoms compared to the risk of contracting COVID-19. Such attitudes may underscore a willingness of patients to continue their DMT where benefits outweigh risks during future phases of the COVID-19 pandemic.

Multiple sclerosis (MS) is an unpredictable, chronic neurological disease accompanied with high rates of depression and anxiety, particularly in the early stages of diagnosis. There is evidence to suggest that cognitive behavioural therapy (CBT) is effective for the treatment of depression amongst individuals with MS; however, there is a paucity of tailored CBT interventions designed to be offered in the newly diagnosed period. This trial is the first to assess the effectiveness and cost-effectiveness of a tailored CBT intervention compared to a supportive listening (SL) intervention amongst individuals with MS who are depressed.ACTION-MS is a two-arm parallel group, assessor-blinded, active comparator, randomised controlled trial which will test whether a tailored CBT-based intervention compared to an SL intervention can reduce depression and related factors such as anxiety, fatigue, pain and sleep problems in those newly diagnosed with MS. Sixty participants who are within 5 years of having received a diagnosis of MS and scored within the mild to moderate range of depression on the Beck Depression Inventory (BDI-II) will be recruited from MS clinics located across three hospital sites in Melbourne, Australia. The primary outcome is depression severity using the BDI-II at post-assessment. Intervention satisfaction and acceptability will be assessed. A cost-effectiveness analysis will also be conducted. Data will be analysed on an intention-to-treat basis.There is a scarcity of psychological interventions for depression targeting the newly diagnosed period. However, interventions during this time point have the potential to have a major impact on the mental and physical wellbeing of those newly diagnosed with MS. The current trial will provide data on the effectiveness of a tailored CBT intervention for the treatment of depression in those newly diagnosed with MS. Findings will also provide effect size estimates that can be used to power a later-stage multi-centre trial of treatment efficacy, and will provide information on the mechanisms underlying any treatment effects and cost-effectiveness data for delivering this intervention in outpatient MS clinics.ISRCTN trials registry, ISRCTN63987586. Current controlled trials. Retrospectively registered on 20 October 2017.

Objective The objective of this study was to evaluate the regulatory dynamics between stress and fatigue experienced by women during the menopausal transition (MT) and early postmenopause (EPM). Fatigue and perceived stress are commonly experienced by women during the MT and EPM. We sought to discover relationships between these symptoms and to employ these symptoms as possible markers for resilience. Methods Participants were drawn from the longitudinal Seattle Midlife Women's Health Study. Eligible women completed questionnaires on 60+ occasions (annual health reports and monthly health diaries) (n = 56 women). The total number of observations across the sample was 4,224. STRAW+10 criteria were used to stage women in either in late reproductive, early or late transition, or EPM stage. Change values were generated for fatigue and stress and analyzed with a multilevel structural equation model; slopes indicate how quickly a person returns to homeostasis after a perturbation. Coupling of stress and fatigue was modeled to evaluate resilience, the notion of maintaining stability during change. Results Eligible women were on average 35 years old (SD = 4.71), well educated, employed, married or partnered, and white. Fit indices suggested the model depicts the relationships of stress and fatigue (χ(9 df) = 7.638, P = 0.57, correction factor = 4.9244; root mean square error of approximation (RMSEA) 90% CI = 0.000 ≤ 0.000 ≤ 0.032; comparative fit index (CFI) = 1.00). A loss in model fit across stages suggests that the four stages differed in their dynamics (χΔ(12 df) = 21.181, P = .048). All stages showed fixed-point attractor dynamics: fatigue became less stable over time; stress generally became more stable over time. Coupling relationships of stress on fatigue show evidence for shifts in regulatory relationships with one another across the MT. Conclusions Results are suggestive of general dysregulation via disruptions to coupling relationships of stress and fatigue across the MT. Findings support a holistic approach to understanding symptoms and supporting women during the MT.

Multiple sclerosis (MS) is usually diagnosed in women during their childbearing years. Currently, no consensus exists on whether pregnancy can delay the first episode of demyelination or clinically isolated syndrome (CIS).To investigate the association of pregnancy with time to CIS onset.This multicenter cohort study collected reproductive history (duration of each pregnancy, date of delivery, length of breastfeeding) on all participants between September 1, 2016, and June 25, 2019. Adult women being treated at the MS outpatient clinics of 4 tertiary hospitals in 2 countries (Charles University and General University Hospital in Prague, Czech Republic; Royal Melbourne Hospital in Melbourne, Australia; Alfred Hospital in Melbourne, Australia; and John Hunter Hospital in Newcastle, Australia) were recruited to participate in the study. Preexisting data (date of CIS onset, date of birth, sex, date of clinical onset, and Expanded Disability Status Scale result) were collected from MSBase, an international registry of long-term prospectively collected data on patients with MS. Data analyses were performed from June 1, 2019, to February 3, 2020.Gravida (defined as any pregnancy, including pregnancy that ended in miscarriage and induced abortion) and parity (defined as childbirth after gestational age of more than 20 weeks, including livebirth and stillbirth) before CIS onset.Time to CIS onset. The following were assessed: (1) whether women with previous pregnancies and childbirths had a delayed onset of CIS compared with those who had never been pregnant and those who had never given birth, and (2) whether a dose response existed, whereby a higher number of gravidity and parity was associated with a later onset of CIS.Of the 2557 women included in the study, the mean (SD) age at CIS onset was 31.5 (9.7) years. Of these women, before CIS onset, 1188 (46%) had at least 1 pregnancy and 1100 (43%) had at least 1 childbirth. The mean (SD) age at first pregnancy was 23.3 (4.5) years and at first childbirth was 23.8 (4.5) years. Women with previous pregnancies and childbirths had a later onset of CIS compared with those who had never been pregnant (HR, 0.68; 95% CI, 0.62-0.75; P .001), with a median delay of 3.3 (95% CI, 2.5-4.1) years. Women who had given birth also had a later CIS onset compared with women who had never given birth (HR 0.68; 95% CI, 0.61-0.75; P .001), with a similar median delay of 3.4 (95% CI, 1.6-5.2) years. A higher gravidity and parity number was not associated with delay in CIS onset.This study suggests an association between previous pregnancies and childbirths and timing of CIS onset, but having more pregnancies or childbirths did not appear to be associated with a later CIS onset. Further studies are needed to help explain the mechanisms behind the associations between pregnancy and onset of multiple sclerosis.

Background: The COVID-19 pandemic challenges multiple sclerosis services to be innovative in delivering infusible therapies. To reduce time in clinical settings, and potential staff or space losses, we implemented rapid infusion protocols for selected patients. Objective: To analyse the rate of infusion related reactions and patient experience of rapid infusions of natalizumab and ocrelizumab. To document time reduction patients spent in clinical settings during the COVID-19 pandemic. Methods: Patients with prior exposure to at least three natalizumab or two 300mg ocrelizumab infusions were approved for rapid protocols. A retrospective audit and survey were completed. Results: We analysed 269 rapid natalizumab infusions and 100 rapid ocrelizumab infusions. Infusion related reactions during the natalizumab or ocrelizumab infusions occurred in two patients (1.52%) and eight patients (8%), respectively. All infusion related reactions were mild to moderate and did not require infusion discontinuation. No infusion reactions occurred during the post-infusion observation. Patient experience was positive. Conclusion: Frequency or severity of infusion related reactions in rapid infusions were no different compared to published data. In the setting of COVID-19, pandemic rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis.

Opioid misuse is a problem that is complex and widespread. Opioid misuse rates are rising across all US demographics, including among pregnant women. The opioid epidemic brings a unique set of challenges for maternity health care providers, ranging from ethical considerations to the complex health needs and risks for both woman and fetus. This article addresses care for pregnant women during the antepartum, intrapartum, and postpartum periods through the lens of the opioid epidemic, including screening and counseling, an interprofessional approach to prenatal care, legal considerations, and considerations for care during labor and birth and postpartum. Providers can be trained to identify at-risk women through the evidence-based process of Screening, Brief Intervention, and Referral to Treatment (SBIRT) and connect them with the appropriate care to optimize outcomes. Women at moderate risk of opioid use disorder can be engaged in a brief conversation with their provider to discuss risks and enhance motivation for healthy behaviors. Women with risky opioid use can be given a warm referral to pharmacologic treatment programs, ideally comprehensive prenatal treatment programs where available (a warm referral is a term used when a provider, with the patient's permission, contacts another provider or another service him or herself rather than providing a phone number and referral number). Evidence regarding care for the pregnant woman with opioid use disorder and practical clinical recommendations are provided.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

Objective: To qualitatively categorize Traditional Chinese Medicine (TCM) differential diagnoses in a sample of veterans with Gulf War Illness (GWI) pre- and postacupuncture treatment. Subjects and methods: The authors randomized 104 veterans diagnosed with GWI to a 6-month acupuncture intervention that consisted of either weekly or biweekly individualized acupuncture treatments. TCM differential diagnoses were recorded at baseline and at 6 months. These TCM diagnoses were evaluated using Matrix Analysis to determine co-occurring patterns of excess, deficiency, and channel imbalances. These diagnoses were examined within and between participants to determine patterns of change and to assess stability of TCM diagnoses over time. Results: Frequencies of diagnoses of excess, deficiency, and channel patterns were tabulated. Diagnoses of excess combined with deficiency decreased from 43% at baseline to 39% of the sample at 6 months. Excess+deficiency+channel imbalances decreased from 26% to 17%, while deficiency+channel imbalances decreased from 11% to 4% over the study duration. The authors observed a trend over time of decreased numbers of individuals presenting with all three types of differential diagnosis combinations. This may suggest that fewer people were diagnosed with concurrent excess, deficiency, and channel imbalances and perhaps a lessening in the complexity of their presentation. Conclusion: This is the first published article that organizes and defines TCM differential diagnoses using Matrix Analysis; currently, there are no TCM frameworks for GWI. These findings are preliminary given the sample size and the amount of missing data at 6 months. Characterization of the TCM clinical presentation of veterans suffering from GWI may help us better understand the potential role that East Asian medicine may play in managing veterans with GWI and the design of effective acupuncture treatments based on TCM. The development of a TCM manual for treating GWI is merited.

Pressures for cost-effective new therapies and an increased emphasis on emerging markets require technological advancements and a flexible future manufacturing network for the production of biologic medicines. The safety and efficacy of a product is crucial, and consistent product quality is an essential feature of any therapeutic manufacturing process. The active control of product quality in a typical biologic process is challenging because of measurement lags and nonlinearities present in the system. The current study uses nonlinear model predictive control to maintain a critical product quality attribute at a predetermined value during pilot scale manufacturing operations. This approach to product quality control ensures a more consistent product for patients, enables greater manufacturing efficiency, and eliminates the need for extensive process characterization by providing direct measures of critical product quality attributes for real time release of drug product. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:1433–1441, 2015

Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer’s disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.

Review controlled clinical trials of isoflavones and amino acid preparation effects on hot flashes and at least one other symptom including mood, sleep, pain, and cognitive function that women report during the menopausal transition and early postmenopause.An experienced reference librarian searched PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for English-language randomized controlled trials between 2004 and July 2011. Seventeen trials of isoflavones and amino acid effects on hot flashes and one additional symptom were identified.In five trials of soy isoflavone preparations, two (6g soy germ extract and 25 g soy protein in soy nuts) significantly decreased hot flashes, but no other symptoms. In the seven trials of other isoflavones, six significantly reduced hot flashes; in addition, red clover (80 mg) significantly reduced mood symptoms; Rexflavone (350 mg) for women with Kupperman Index20 significantly reduced sleep symptoms; two trials had significant reductions for pain: isoflavone powder (90 mg) and red clover (80 mg). The only trial in this systematic review that significantly reduced cognitive symptoms was red clover (80 mg). In one trial, red clover isoflavone (80 mg/day) significantly relieved hot flashes, mood, pain, and cognitive symptoms. Amino acids yielded no significant results. Equol supplements of 30 mg/day for non-Equol producing women significantly reduced mood symptoms in one trial. The magnolia bark extract combination significantly reduced hot flashes, mood, and sleep symptoms.Isoflavone trials yielded significant reductions on hot flashes and co-occurring symptoms during the menopausal transition and postmenopause, but studies require replication with larger sample sizes and attention to measurement of outcomes.

To determine the effects of herbal therapies on hot flushes and at least one other symptom including, sleep, mood, cognition, and pain that women experience during the menopausal transition and early postmenopause.An extensive search of PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for randomized, controlled trials reported in English between January 2004 and July was conducted by an experienced reference librarian. There were 1193 abstracts identified but only 58 trials examined effectiveness of therapies for hot flushes and at least one additional co-occurring symptom.Seventeen studies used herbal preparation including seven studies of black cohosh, two studies of black cohosh mixed with other herbals, and eight studies of other herbals. Of these, one study of black cohosh, two studies of black cohosh mixed with other herbals, and four other herbal studies had significant effects on hot flushes and at least one additional co-occurring symptom. The adverse events of herbal therapies were various, ranging from mild to moderate and women were generally tolerant of the preparations.Black cohosh mixed with other herbals, Rheum rhaponticum, and French maritime pine bark had significant effects on hot flushes and at least one other symptom. These herbal therapies may be a promising alternative treatment to hormonal treatment. Future studies should classify women based on their menopausal stages, report each symptom separately, have adequate sample size, focus on multiple co-occurring symptoms, and target symptom management of menopausal symptoms.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

This study investigated similarities and differences in the experience of auditory hallucinations, paranoia, and childhood trauma in schizophrenia and borderline personality disorder (BPD). Patients with clinical diagnoses of schizophrenia or BPD were interviewed using the Structured Clinical Interviews for DSM-IV. Axes 1 and 2 and auditory hallucinations, paranoia, and childhood trauma were assessed. A total of 111 patients participated; 59 met criteria for schizophrenia, 33 for BPD, and 19 for both. The groups were similar in their experiences of voices, including the perceived location of them, but they differed in frequency of paranoid delusions. Those with a diagnosis of BPD, including those with schizophrenia comorbidity, reported more childhood trauma, especially emotional abuse. BPD and schizophrenia frequently coexist, and this comorbidity has implications for diagnostic classification and treatment. Levels of reported childhood trauma are especially high in those with a BPD diagnosis, whether they have schizophrenia or not, and this requires assessment and appropriate management.

Our objectives are to facilitate autopsy consent, brain collection, and perform standardized neuropathologic assessments of all Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who come to autopsy at the 58 ADNI sites in the USA and Canada.Building on the expertise and resources of the existing Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, MO, a Neuropathology Core (NPC) to serve ADNI was established with one new highly motivated research coordinator. The ADNI-NPC coordinator provides training materials and protocols to assist clinicians at ADNI sites in obtaining voluntary consent for brain autopsy in ADNI participants. Secondly, the ADNI-NPC maintains a central laboratory to provide uniform neuropathologic assessments using the operational criteria for the classification of AD and other pathologies defined by the National Alzheimer Coordinating Center (NACC). Thirdly, the ADNI-NPC maintains a state-of-the-art brain bank of ADNI-derived brain tissue to promote biomarker and multi-disciplinary clinicopathologic studies.During the initial year of funding of the ADNI Neuropathology Core, there was notable improvement in the autopsy rate to 44.4%. In the most recent year of funding (September 1(st), 2008 to August 31(st) 2009), our autopsy rate improved to 71.5%. Although the overall numbers to date are small, these data demonstrate that the Neuropathology Core has established the administrative organization with the participating sites to harvest brains from ADNI participants who come to autopsy.Within two years of operation, the Neuropathology Core has: (1) implemented a protocol to solicit permission for brain autopsy in ADNI participants at all 58 sites who die and (2) to send appropriate brain tissue from the decedents to the Neuropathology Core for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI of the implementation of the NPC is very clear. Prior to the establishment of the NPC in September 2007, there were 6 deaths but no autopsies in ADNI participants. Subsequent to the establishment of the Core there have been 17 deaths of ADNI participants and 10 autopsies. Hence, the autopsy rate has gone from 0% to 59%. The third major accomplishment is the detection of co-existent pathologies with AD in the autopsied cases. It is possible that these co-morbidities may contribute to any variance in ADNI data.

Objective: To investigate the specificity of in vivo amyloid imaging with [ 11 C]–Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD). Methods: We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death. Results: We observed elevated cortical uptake of [ 11 C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Aβ plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden. Conclusions: [ 11 C]–Pittsburgh Compound B (PIB) PET is specific for fibrillar Aβ molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Aβ amyloid in the setting of α-synucleinopathy makes [ 11 C]-PIB PET a valuable tool for prospectively evaluating how the presence of Aβ amyloid influences the clinical course of dementia in patients with Lewy body disorders.

Frontotemporal lobar degeneration (FTLD) with inclusion body myopathy and Paget disease of bone is a rare, autosomal dominant disorder caused by mutations in the VCP (valosin-containing protein) gene. The disease is characterized neuropathologically by frontal and temporal lobar atrophy, neuron loss and gliosis, and ubiquitin-positive inclusions (FTLD-U), which are distinct from those seen in other sporadic and familial FTLD-U entities. The major component of the ubiquitinated inclusions of FTLD with VCP mutation is TDP-43 (TAR DNA-binding protein of 43 kDa). TDP-43 proteinopathy links sporadic amyotrophic lateral sclerosis, sporadic FTLD-U, and most familial forms of FTLD-U. Understanding the relationship between individual gene defects and pathologic TDP-43 will facilitate the characterization of the mechanisms leading to neurodegeneration. Using cell culture models, we have investigated the role of mutant VCP in intracellular trafficking, proteasomal function, and cell death and demonstrate that mutations in the VCP gene 1) alter localization of TDP-43 between the nucleus and cytosol, 2) decrease proteasome activity, 3) induce endoplasmic reticulum stress, 4) increase markers of apoptosis, and 5) impair cell viability. These results suggest that VCP mutation-induced neurodegeneration is mediated by several mechanisms.

TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.

Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant A[beta] plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.

Background\ud The review undertaken revealed that there is an abundance of literature concerning retention and the high levels of attrition among undergraduate students and of relevance here, nurse education. The study undertaken evaluated the use of mobile phone automated texts designed to provide information, support and reassurance to help alleviate the stress and anxieties that some undergraduate nursing students experience during the early phase of their studies and which can lead to some students leaving their programme.\ud \ud Objective\ud The objective of the study was to evaluate how use of automated mobile phone texts, using a system known as FLO, could usefully supplement pastoral support, as an intervention to reduce attrition among undergraduate nursing students.\ud \ud Design\ud A qualitative and quantitative evaluation was conducted using an open-ended questionnaire designed specifically for the study.\ud \ud Participants\ud The sample were two cohorts of undergraduate first year student nurses (n = 178). Of these 123 (69%) signed up to FLO and 77 (63%) completed the evaluation form.\ud \ud Methods\ud The evaluation form that was administered in a classroom situation one week after use of FLO had ceased. Data were analysed through use of a descriptive statistics and thematic analysis approaches.\ud \ud Results\ud A range of key themes emerged from the analysis including that text messages were helpful and supportive, increased a sense of belonging to the University and encouraged retention. There were some unresolved issues concerning the costs incurred by participants when sending reply text messages.\ud \ud Conclusions\ud It is concluded that FLO or use of similar mobile phone protocols can be a useful addition to approaches to improve undergraduate nursing student retention rates.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Previous reports of cognitive functioning in children with the 22q11 Deletion Syndrome have reported marked variability in IQ and achievement subtest scores. Studies have begun to explore neuropsychological function in 22q11 DS however results are inconsistent and the profile incomplete. We assessed 40 children ages 5–12 with 22q11 DS. Consistent with past results, visual-spatial memory was significantly lower than verbal memory. Differentially lowered scores were found only in visual attention, working memory and motor function. Contrary with some past results quantitative, verbal ability, and visual spatial memory scores were within 1 SD from the standardization sample mean. Motor behavior, not typically discussed with regard to 22q11 DS school-age children, may be critical to incorporate in neurocognitive studies of children with 22q11 DS. Implications of these findings are considered with regard to past results.

Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.

Understanding binding properties at protein–protein interfaces has been limited to structural and mutational analyses of natural binding partners or small peptides identified by phage display. Here, we present a high-resolution analysis of a nonpeptidyl small molecule, previously discovered by medicinal chemistry [Tilley, J. W., et al . (1997) J. Am. Chem. Soc. 119, 7589–7590], which binds to the cytokine IL-2. The small molecule binds to the same site that binds the IL-2 α receptor and buries into a groove not seen in the free structure of IL-2. Comparison of the bound and several free structures shows this site to be composed of two subsites: one is rigid, and the other is highly adaptive. Thermodynamic data suggest the energy barriers between these conformations are low. The subsites were dissected by using a site-directed screening method called tethering, in which small fragments were captured by disulfide interchange with cysteines introduced into IL-2 around these subsites. X-ray structures with the tethered fragments show that the subsite-binding interactions are similar to those observed with the original small molecule. Moreover, the adaptive subsite tethered many more compounds than did the rigid one. Thus, the adaptive nature of a protein–protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface.

To review controlled clinical trials of traditional Chinese medicine (TCM) therapies for hot flushes and at least one other co-occurring symptom among sleep, cognitive function, mood, and pain.An experienced reference librarian performed an extensive search of PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for randomized, controlled trials reported in English between 2004 and July 2011. Of 1193 abstracts identified, 58 trials examined effectiveness of therapies for hot flushes and at least one additional co-occurring symptom.Eleven trials (13 publications) examined TCM therapeutics of acupuncture, Chinese herbal medicine (CHM) or moxibustion. Acupuncture trials (eight) yielded mixed results; five trials significantly reduced hot flushes. Of those five trials, one also showed benefit for sleep and pain and two trials found benefit for mood symptoms. Of three CHM trials, three trials had significant findings: one for hot flushes and mood, one for hot flushes and pain, and one for hot flushes, sleep, mood symptoms and pain. Moxibustion and counseling (one trial) significantly reduced hot flushes, mood symptoms and pain. None of the trials reported any serious adverse events.TCM therapeutics of acupuncture, CHM and moxibustion show promising results for the treatment of mood and pain symptoms co-occurring with hot flushes. Although the controlled clinical trials of TCM therapeutics reviewed here measured multiple symptom outcomes, few report treatment effects in ways that allow clinicians to consider symptom clusters when prescribing therapies. Future studies need to measure and report results for individual symptoms or group like symptoms together into subscales. Controlled clinical trials with larger numbers of participants are essential to allow evaluation of these therapies on hot flushes and multiple co-occurring symptoms.

There is a lack of studies looking at variation of behavioral stuttering among various cultures. This study compared verbal disfluency and accessory characteristics of 15 African American and 15 White male stutterers between the ages of 8 and 12. In addition to a speaking attitude scale for each of the subjects, conversational and reading samples were gathered. Good intra- and inter-judge reliability was found in assessing the various tasks. Overall results revealed no statistically significant differences in verbal or visual disfluency behaviors on either the reading or conversation tasks between the African American and White groups of children. In addition, no differences in attitudes toward speaking situations was found between the two groups of children. Implications for the diagnosis and treatment of disfluent African American elementary school aged children are discussed. Specific suggestions are made for additional disfluency research with African American children.

The 1995 Peritoneal Dialysis Core Indicators Study was conducted by the Health Care Financing Administration to ascertain standard practices and outcomes in chronic peritoneal dialysis patients. Data from 1,202 patients who did not receive hemodialysis but who were on chronic ambulatory peritoneal dialysis (CAPD) for at least part of the 6-month period between November 1, 1994, and April 30, 1995, are reported. The mean serum albumin level for this cohort was 3.5 g/dL by the bromcresol green method and 3.2 g/dL by the bromcresol purple method. Data sufficient to calculate a weekly Kt/V urea or weekly creatinine clearance were available for only 34% of patient submissions. In these patients, the median weekly Kt/V urea was 1.7 using a fixed value for V of 0.58 × body weight and was 2.0 using the Watson equation to calculate V, the median weekly creatinine clearance was 60.7 L/wk/1.73 m 2 . The mean hematocrit for this cohort was 32% and the average weekly recombinant human erythropoietin (rHmEPO) dose was 115 μ/ kg. Hematocrit values ≤30% were found in 50% of black patients and 31% of white patients. The average blood pressure among peritoneal dialysis patients was 139/80 mm Hg, with 29% of patients having a systolic blood pressure exceeding 150 mm Hg and 18% a diastolic blood pressure greater than 90 mm Hg. In summary, serum albumin levels were significantly lower in peritoneal dialysis patients than in hemodialysis patients. Approximately one third of peritoneal dialysis patients did not have an adequacy measure obtained during the 6-month observation period. A significant minority of patients had either inadequately treated anemia of chronic renal disease or hypertension. There is an opportunity to substantially improve the medical care provided to chronic peritoneal dialysis patients.

Although most women experience symptom clusters during the menopausal transition and early postmenopause, investigators reporting clinical trial effects for hot flushes often omit co-occurring symptoms. Our aim was to review controlled clinical trials of mind-body therapies for hot flushes and at least one other co-occurring symptom from these groups: sleep, cognitive function, mood, and pain.An experienced reference librarian performed an extensive search of PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for randomized controlled trials reported in English between 2004 and July 2011. Of 1193 abstracts identified, 58 trials examining effectiveness of therapies for hot flushes and at least one additional co-occurring symptom of interest were identified.Eight trials (ten publications) examined relaxation, yoga, or exercise. Physical activity/exercise trials (six) yielded mixed results; only one significantly reduced hot flushes and mood symptoms. Of two relaxation therapy trials, only mindfulness-based stress reduction training reduced sleep and mood symptoms and had within-group treatment effects on hot flushes. Yoga (one trial) significantly reduced hot flushes and improved cognitive symptoms more than exercise, and also had within-group effects on sleep and pain symptoms.Studies of mind-body therapies for hot flushes increasingly measure multiple symptom outcomes, but few report treatment effects in ways that allow clinicians to consider symptom clusters when prescribing therapies. Future studies need to measure and report results for individual symptoms or group like symptoms together into subscales rather than use subscales with mixed dimensions. Trials with larger numbers of participants are essential to allow evaluation of these therapies on multiple co-occurring symptoms.

In 2007, Craig et al. reported the results of a randomized controlled trial in which a standardized acupuncture protocol performed on the day of embryo transfer (ET) resulted in lower pregnancy rates after in vitro fertilization (IVF). Between 2005 and 2007, the Craig protocol was used by one of the authors (LHR) at an infertility clinic unaffiliated with the Craig et al. trial. The objective was to retrospectively review clinic records to evaluate the effect of the Craig protocol in both donor and nondonor IVF cycles on four outcomes: (1) live births; (2) biochemical pregnancies; (3) adverse outcomes; and (4) live births in nondonor cycles across age groups established by the Society for Assisted Reproductive Technology.The study design was a retrospective chart review.The study was conducted at a private infertility clinic.Patients underwent fresh, donor (N=70) or nondonor (N=402) IVF-ET.The Craig protocol included the following points before ET: GV-20, CV-6, ST-29, SP-8, PC-6, LV-3; Shenmen and Brain on the left ear; and Uterus and Endocrine on the right ear. After transfer the points were LI-4, SP-10, ST-36, SP-6, KI-3; Uterus and Endocrine on the left ear; and Shenmen and Brain on the right ear.Live births (LB) beyond 24 weeks' gestation was the main outcome measure.In nondonor IVF cycles, there were no differences in LB across age groups (odds ratio [OR]=1.04, 95% confidence interval [CI] 0.68-1.57), biochemical pregnancies (OR=0.60, 95% CI 0.27-1.33), or adverse outcomes (OR=0.63, 95% CI 0.31-1.26). In donor cycles, LB were higher in the acupuncture group (relative risk=1.31, 95% CI 1.02-1.71).In this observational study, the Craig protocol was not found to lower IVF LB. In fact, the Craig protocol was associated with higher LB in donor cycles. These findings should be considered cautiously because more adequately powered, randomized research is needed.