Neuroimaging predictors of longitudinal disability and cognition outcomes in multiple sclerosis patients: A systematic review and meta-analysis.

BACKGROUND: Cross-sectional magnetic resonance imaging (MRI) studies have generated substantial evidence relating neuroimaging abnormalities to clinical and cognitive decline in multiple sclerosis (MS). Longitudinal neuroimaging studies may have additional value for predicting future cognitive deficits or clinical impairment, potentially leading to earlier interventions and better disease management. We conducted a meta-analysis of longitudinal studies using neuroimaging to predict cognitive decline (i.e. the Symbol Digits Modalities Test, SDMT) and disability outcomes (i.e. the Expanded Disability Status Scale, EDSS) in MS. METHODS: Our systematic literature search yielded 64 relevant publications encompassing 105 distinct sub-analyses. We performed a multilevel random-effects meta-analysis to estimate overall effect size for neuroimaging's ability to predict longitudinal cognitive and clinical decline, and a meta-regression to investigate the impact of distinct study factors on pooled effect size. RESULTS: In the EDSS analyses, the meta-analysis yielded a medium overall pooled effect size (Pearson's correlation coefficient r = 0.42, 95% CI [0.37; 0.46]). The meta-regression further indicated that analyses exclusively evaluating gray matter tissue had significantly stronger effect sizes than analyses of white matter tissue or whole brain analyses (p < 0.05). No other study factors significantly influenced the pooled effect size (all p > 0.05). In the SDMT analyses, the meta-analysis yielded a medium overall pooled effect size (r = 0.47, 95% CI [0.32; 0.60]). The meta-regression found no significant study factors influencing the pooled effect size. CONCLUSION: The present findings indicate that brain imaging is a medium predictor of longitudinal change in both disability progression (EDSS) and cognitive decline (SDMT). These findings reinforce the need for further longitudinal studies standardizing methods, using multimodal approaches, creating data consortiums, and publishing more complete datasets investigating MRI modalities to predict longitudinal disability and cognitive decline.

Transcriptome and proteome of the corm, leaf and flower of Hypoxis hemerocallidea (African potato).

The corm of Hypoxis hemerocallidea, commonly known as the African potato, is used in traditional medicine to treat several medical conditions such as urinary infections, benign prostate hyperplasia, inflammatory conditions and testicular tumours. The metabolites contributing to the medicinal properties of H. hemerocallidea have been identified in several studies and, more recently, the active terpenoids of the plant were profiled. However, the biosynthetic pathways and the enzymes involved in the production of the terpene metabolites in H. hemerocallidea have not been characterised at a transcriptomic or proteomic level. In this study, total RNA extracted from the corm, leaf and flower tissues of H. hemerocallidea was sequenced on the Illumina HiSeq 2500 platform. A total of 143,549 transcripts were assembled de novo using Trinity and 107,131 transcripts were functionally annotated using the nr, GO, COG, KEGG and SWISS-PROT databases. Additionally, the proteome of the three tissues were sequenced using LC-MS/MS, revealing aspects of secondary metabolism and serving as data validation for the transcriptome. Functional annotation led to the identification of numerous terpene synthases such as nerolidol synthase, germacrene D synthase, and cycloartenol synthase amongst others. Annotations also revealed a transcript encoding the terpene synthase phytoalexin momilactone A synthase. Differential expression analysis using edgeR identified 946 transcripts differentially expressed between the three tissues and revealed that the leaf upregulates linalool synthase compared to the corm and the flower tissues. The transcriptome as well as the proteome of Hypoxis hemerocallidea presented here provide a foundation for future research.

Primary mediastinal large B-cell lymphoma in a patient on Fingolimod for relapsing-remitting multiple sclerosis.

BACKGROUND: There are multiple case reports in the literature describing an association between fingolimod and cutaneous neoplasms. OBJECTIVE: Investigate and report a case of a primary mediastinal large B-cell lymphoma in a patient on fingolimod for Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: Case Report. RESULTS: The patient developed a primary mediastinal large B-cell lymphoma after seven years of treatment with fingolimod. The patient is currently in complete remission after cessation of treatment, surgical resection, chemotherapy, and radiation therapy. CONCLUSION: This case report highlights the first primary mediastinal large B-cell lymphoma associated with fingolimod treatment. It should be considered a rare, but potential adverse effect of fingolimod.

Immunosuppression in chronic autoimmune neurological disorders during the COVID-19 pandemic.

OBJECTIVE: To study the risk of acquiring Corona Virus Disease 2019 (COVID-19) and its outcomes in patients on immunosuppressive therapy (IST) for chronic autoimmune neuromuscular disorders (aNMD) and multiple sclerosis (MS). METHODS: We used TriNetX, a global health collaborative clinical research platform collecting real-time electronic medical records data, which has one of the largest known global COVID-19 database. We included patients with chronic autoimmune neuromuscular disorders (aNMD) [myasthenia gravis (MG), inflammatory myositis, and chronic inflammatory neuropathies (CIN)] and MS, based on the International Classification of Disease-10 (ICD-10) coding for one year before January 20th, 2020. We examined the use of IST, rate of COVID- 19, hospitalization, intubation, and mortality among the patients with aNMD and MS. RESULTS: A total of 33,451 patients with aNMD and 42,899 patients with MS were included. Among them, 111 (0.33%) patients with aNMD and 115 patients (0.27%) with MS had COVID-19. About one third of them required hospitalization. IST did not appear to have a significant impact on overall infection risk in either group; however, risk of hospitalization for immunosuppressed patients with aNMD was higher (Odds ratio 2.86, p-value 0.011). CONCLUSIONS: IST use does not appear to make patients with aNMD and MS more vulnerable to COVID-19. IST may be continued during the pandemic, as previously suggested by expert opinion guidelines. However, it is important to consider individualizing immunotherapy regimens in some cases. Additional physician reported registry-based data is needed to further confirm these findings.

Functional characterisation of the transcriptome from leaf tissue of the fluoroacetate-producing plant, Dichapetalum cymosum, in response to mechanical wounding.

Dichapetalum cymosum produces the toxic fluorinated metabolite, fluoroacetate, presumably as a defence mechanism. Given the rarity of fluorinated metabolites in nature, the biosynthetic origin and function of fluoroacetate have been of particular interest. However, the mechanism for fluorination in D. cymosum was never elucidated. More importantly, there is a severe lack in knowledge on a genetic level for fluorometabolite-producing plants, impeding research on the subject. Here, we report on the first transcriptome for D. cymosum and investigate the wound response for insights into fluorometabolite production. Mechanical wounding studies were performed and libraries of the unwounded (control) and wounded (30 and 60 min post wounding) plant were sequenced using the Illumina HiSeq platform. A combined reference assembly generated 77,845 transcripts. Using the SwissProt, TrEMBL, GO, eggNOG, KEGG, Pfam, EC and PlantTFDB databases, a 69% annotation rate was achieved. Differential expression analysis revealed the regulation of 364 genes in response to wounding. The wound responses in D. cymosum included key mechanisms relating to signalling cascades, phytohormone regulation, transcription factors and defence-related secondary metabolites. However, the role of fluoroacetate in inducible wound responses remains unclear. Bacterial fluorinases were searched against the D. cymosum transcriptome but transcripts with homology were not detected suggesting the presence of a potentially different fluorinating enzyme in plants. Nevertheless, the transcriptome produced in this study significantly increases genetic resources available for D. cymosum and will assist with future research into fluorometabolite-producing plants.

Conversion Disorder: Early Diagnosis and Personalized Therapy Plan Is the Key.

Conversion disorder is characterized by one or more symptoms of altered voluntary motor or sensory functions that cannot be explained by a neurological disease (Keynejad, 2019; Samuels et al., 2019). We present a patient with conversion disorder and discuss her process in overcoming this disorder. Additionally, we review the literature about this specific disorder. A 15-year-old white female was diagnosed with conversion disorder and has shown significant recovery with physical therapy and group therapy since. It is essential to recognize this disorder early to lessen the financial burden on families and to speed up the recovery process for these patients.

Complex sternal and rib reconstruction with allogeneic material.

Sternal malunion, or loss, developed after a median sternotomy cannot only be difficult to manage and treat, but also may diminish one's quality-of-life drastically. The technique presented here represents a multispecialty approach in one stage for the reconstruction of an unstable thoracic cage. The procedure utilized a donated sternum and ribs. The sternum with ribs harvested from a single donor included adipose derived stromal vascular fraction (ADSVF) cells with marrow also from the same donor. Autologous muscle flaps, stabilized with acellular dermal matrix were utilized to provide a robust blood supply to the ADSVF cells and bone grafts. Acellular dermal matrix was used to construct the ribs and stabilize the plugs of stem cells and bone. These procedures, in the hands of multispecialty physicians, have led to several successful reconstructions involving complex chest wall deformities. This surgical intervention was performed in a one stage operation. This represents the first successful complete sternal transplant in a patient with return to normal activities and increased quality-of-life.

Perceived school safety, perceived neighborhood safety, and insufficient sleep among adolescents.

OBJECTIVES: To examine whether perceptions of school safety and neighborhood safety are associated with insufficient sleep during adolescence. DESIGN: The Florida Youth Substance Abuse Survey (FYSAS) is a cross-sectional study of adolescents. SETTING: The state of Florida. PARTICIPANTS: Middle-school and high-school students (n = 7,958) attending public schools in 2017. MEASUREMENTS: Based on National Sleep Foundation recommendations, sleep was categorized as insufficient (less than 7 hours) or sufficient (7 or more hours) using self-reports of average sleep duration on school nights. Self-reports of perceived safety at school and perceived safety in one's neighborhood were modeled as predictors of insufficient sleep in logistic regression models when accounting for several covariates. RESULTS: Adjusting for model covariates, the odds of insufficient sleep among adolescents who feel unsafe both at school and in their neighborhood are 129% greater relative to adolescents who feel safe in both contexts. In comparison, the odds of insufficient sleep among adolescents who feel unsafe only at school are 39% greater relative to adolescents who feel safe both at school and in their neighborhood, and the odds of insufficient sleep among adolescents who feel unsafe only in their neighborhood are 71% greater relative to adolescents who feel safe both at school and in their neighborhood. CONCLUSIONS: The findings of this study indicate that efforts to improve the safety of salient social contexts in which adolescents develop may reduce the likelihood of insufficient sleep faced by a large portion of school-aged children.

Limitations in the Prediction of Mass Violence: Cautionary Tales.

The incidents of mass violence that have occurred in the United States have been deeply disturbing to the public as well as to mental health professionals. The public, the media, as well as our patients, family members, and friends have reached out to mental health professionals in the hope that we can provide an understanding of these events that might serve to reduce their frequency in the future. This article explores how we can best respond to these requests, including the current limitations of psychologists in the prediction of mass violence. Two incidents of mass violence are used to illustrate these issues. The first is a review of the investigation of the explosion on the U.S.S. Iowa in April 1989 that resulted in the deaths of 47 seamen. The second incident used for illustration purposes will be the University of Texas Clock Tower shootings that occurred in August 1968. This article discusses the reliability and validity problems inherent in retrospective reviews of the personality characteristics of perpetrators, and the limitations imposed by base-rate issues in the prediction of mass violence.

Comparisons between the Minnesota Multiphasic Personality Inventory-Adolescent-Restructured Form (MMPI-A RF) and MMPI-A in adolescent psychiatric inpatients.

This study explored the association between the Minnesota Multiphasic Personality Inventory (MMPI)-Adolescent-Restructured Form (MMPI-A-RF) and the MMPI-Adolescent (MMPI-A) form in a sample of 3,516 adolescents receiving inpatient psychiatric treatment, including 2,798 adolescents meeting validity inclusion cutoffs for both measures. There was 92.5% agreement rate with respect to global identification of cases as valid or invalid and some empirical support for lowering interpretive cutoffs for validity scales on the MMPI-A-RF. The MMPI-A-RF Demoralization Scale (RCd) was shown to correlate significantly less strongly with Restructured Clinical (RC) scales than with MMPI-A clinical scales. RC scales also demonstrated significantly lower mean interscale correlations than MMPI-A clinical scales. As expected, this greater level of scale independence resulted in significantly fewer profiles with multiple scale elevations. As was anticipated, with the exception of RC1 predicting MMPI-A hypochondriasis, correlational and classification agreement analyses suggested moderate associations between the RC and MMPI-A clinical scales, but somewhat stronger agreement between comparable PSY-5 scales. Changes in interpretive cutoff procedures for the RC scales, including RCd, also resulted in 5.5% fewer "within normal limits" profiles than the use of MMPI-A with all 10 clinical scales. Finally, stepwise linear regression analyses indicated that MMPI-A-RF Higher-Order scales were best predicted by those MMPI-A clinical scale combinations that they are purported to be linked with in the MMPI-A-RF manual. (PsycINFO Database Record

Platelet-rich plasma for tissue regeneration can be stored at room temperature for at least five days.

BACKGROUND: Autologous platelet-rich plasma (PRP) is gaining increasing use as a wound healing promoter in a variety of clinical settings, including dentistry. Fresh PRP is often used, necessitating daily draws. The present study investigates the possibility of using stored PRP without having to freeze it by storing PRP under variable conditions and assessing growth factor release as a surrogate marker of continued viability. METHODS: Freshly drawn PRP was stored in oxygen permeable and non-oxygen permeable containers under conditions of constant agitation with or without added prostaglandin, intermittent agitation and no agitation, over an 8-day period. Serial platelet counts, mean platelet volume, platelet distribution width and platelet-large cell ratio, and collagen-induced aggregometry were undertaken. Once collagen-induced aggregation had gone to completion, the plasma was centrifuged to pellet platelet material and the supernatants separated and frozen for batched analysis of released platelet-derived growth factor-BB (PDGF-BB). RESULTS: As would be anticipated, platelet counts, percentage aggregation and PDGF-BB levels all reduced over time. Platelet parameters suggested that platelets were more stable in the non-oxygen permeable containers, possibly due to pH drift and a degree of microaggregate formation in the oxygen permeable containers. CONCLUSION: Although platelet integrity and PDGF-BB fell over time, the intermittently agitated non-oxygen permeable container appeared to retain better platelet integrity and function, and PDGF-BB release, than other storage conditions, with potential for clinical use for 5-8 days.

Biogeography of the Malagasy Celastraceae: Multiple independent origins followed by widespread dispersal of genera from Madagascar.

Of the 97 currently recognized genera of Celastraceae, 19 are native to Madagascar, including six endemics. In this study we conducted the most thorough phylogenetic analysis of Celastraceae yet completed with respect to both character and taxon sampling, and include representatives of five new endemic genera. Fifty-one new accessions, together with 328 previously used accessions of Celastrales, were sampled for morphological characters, two rDNA gene regions, and two plastid gene regions. The endemic Malagasy genera are resolved in two separate lineages-Xenodrys by itself and all other endemic genera in a clade that also includes four lineages inferred to have dispersed from Madagascar: Brexia madagascariensis (Mascarene Islands, coastal Africa), Elaeodendron (West Indies, Africa to New Caledonia), and Pleurostylia (Africa to New Caledonia). Of the 12 extant Malagasy Celastraceae lineages identified, eight are clearly of African origin. The origins of the remaining four lineages are less clear, but reasonable possibilities include America, Eurasia, Africa, southern India, Malesia, and Australia. Based on 95% credible age intervals from fossil-calibrated molecular dating, all 12 extant Malagasy Celastraceae lineages appear to have arisen following dispersal after the separation of Madagascar from other landmasses within the last 70 million years.

Taipan snake venom time coupled with ecarin time enhances lupus anticoagulant detection in nonanticoagulated patients.

A study is presented which assesses the diagnostic impact of incorporating Taipan snake venom time (TSVT) with ecarin time confirmatory test into an existing dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT) repertoire when testing nonanticoagulated patients for lupus anticoagulants. A total of 387 plasma samples from nonanticoagulated patients being investigated for antiphospholipid antibodies were tested for lupus anticoagulant by dRVVT and dilute APTT with confirmatory and mixing tests, and TSVT with ecarin time, with commercially available reagents. All were analyzed on a Sysmex CS2000i automated analyzer. Lupus anticoagulant was not detected by dRVVT, dilute APTT or TSVT screening in 265 of 387 (68.5%) samples. A lupus anticoagulant was detected in 60 (15.5%) samples in dRVVT and/or dilute APTT analysis, but gave normal TSVT ratios. Thirty-nine (10.1%) were positive by TSVT and ecarin time and one or both of dRVVT and dilute APTT testing, whereas a further 23 (5.9%) were only positive in TSVT/ecarin time testing. Most of the lupus anticoagulants manifested in dRVVT and/or APTT analysis, as might be anticipated for this reagent pairing. The samples positive by TSVT/ecarin time only, as has been previously demonstrated, emphasize that the many variables that impact lupus anticoagulant testing mean that even a well established dRVVT and APTT pairing cannot deliver diagnostic certainty. Interference by direct factor Xa inhibitors in dRVVT testing could pave the way for wider adoption of TSVT screening as we gain more evidence of its diagnostic performance.

Neuromyelitis Optica Spectrum Disorder in a Pediatric Patient.

Neuromyelitis optica in the pediatric population is rare. Patients present with acute neurological deficits predominantly involving the optic nerves and spinal cord, usually with a relapsing course. Clinical overlap between multiple sclerosis and other autoimmune disorders can occur and must be ruled out as NMO requires a more aggressive treatment plan. We present a pediatric patent with NMO spectrum disorder in order to draw awareness to this potentially neurologi- cally devastating disease.

Identification and characterization of 2-keto-3-deoxygluconate kinase and 2-keto-3-deoxygalactonate kinase in the haloarchaeon Haloferax volcanii.

The halophilic archaeon Haloferax volcanii has been proposed to degrade glucose via the semi-phosphorylative Entner-Doudoroff pathway, involving 2-keto-3-deoxygluconate kinase (KDGK) as key enzyme. So far, neither the enzyme has been characterized nor the encoding gene has been identified. In the genome of H. volcanii, two genes, HVO_0549 (kdgK1) and HVO_A0328 (kdgK2), are annotated encoding putative KDGK-1 and KDGK-2. To identify the physiological role of both kinases, transcriptional regulation analyses of both genes and growth experiments of the respective deletion mutants were performed on different sugars. Further, recombinant KDGK-1 and KDGK-2 were characterized. Together, the data indicate that KDGK-1 represents the functional constitutively expressed KDG kinase in glucose degradation, whereas KDGK-2 is an inducible 2-keto-3-deoxygalactonate kinase likely involved in d-galactose catabolism.

Syntheses of 2-keto-3-deoxy-D-xylonate and 2-keto-3-deoxy-L-arabinonate as stereochemical probes for demonstrating the metabolic promiscuity of Sulfolobus solfataricus towards D-xylose and L-arabinose.

Practical syntheses of 2-keto-3-deoxy-D-xylonate (D-KDX) and 2-keto-3-deoxy-L-arabinonate (L-KDA) that rely on reaction of the anion of ethyl 2-[(tert-butyldimethylsilyl)oxy]-2-(dimethoxy phosphoryl) acetate with enantiopure glyceraldehyde acetonide, followed by global deprotection of the resultant O-silyl-enol esters, have been developed. This has enabled us to confirm that a 2-keto-3-deoxy-D-gluconate aldolase from the archaeon Sulfolobus solfataricus demonstrates good activity for catalysis of the retro-aldol cleavage of both these enantiomers to afford pyruvate and glycolaldehyde. The stereochemical promiscuity of this aldolase towards these enantiomeric aldol substrates confirms that this organism employs a metabolically promiscuous pathway to catabolise the C5-sugars D-xylose and L-arabinose.

MMPI-2-RF characteristics of custody evaluation litigants.

The Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) is a 338-item objective self-report measure drawn from the 567 items of the MMPI-2. Although there is a substantial MMPI-2 literature regarding child custody litigants, there has been only one previously published study using MMPI-2-RF data in this population that focused on Validity scales L-r and K-r. The current study evaluated the MMPI-2-RF results of 344 child custody litigants and showed substantial consistency between T-score elevations typically found on MMPI-2 Validity scales L and K, and comparable elevations for MMPI-2-RF validity scales L-r and K-r. Mean T-scores well within normal limits characterized results for clinical scales on both instruments. The RC scale intercorrelation patterns, and alpha coefficient values found for MMPI-2-RF scales in a custody population, were also found to be very similar to those reported for other populations. Directions for future research are presented.