Invited Review: The spectrum of neuropathology in COVID-19.

There is increasing evidence that patients with Coronavirus disease 19 (COVID-19) present with neurological and psychiatric symptoms. Anosmia, hypogeusia, headache, nausea and altered consciousness are commonly described, although there are emerging clinical reports of more serious and specific conditions such as acute cerebrovascular accident, encephalitis and demyelinating disease. Whether these presentations are directly due to viral invasion of the central nervous system (CNS) or caused by indirect mechanisms has yet to be established. Neuropathological examination of brain tissue at autopsy will be essential to establish the neuro-invasive potential of the SARS-CoV-2 virus but, to date, there have been few detailed studies. The pathological changes in the brain probably represent a combination of direct cytopathic effects mediated by SARS-CoV-2 replication or indirect effects due to respiratory failure, injurious cytokine reaction, reduced immune response and cerebrovascular accidents induced by viral infection. Further large-scale molecular and cellular investigations are warranted to clarify the neuropathological correlates of the neurological and psychiatric features seen clinically in COVID-19. In this review, we summarize the current reports of neuropathological examination in COVID-19 patients, in addition to our own experience, and discuss their contribution to the understanding of CNS involvement in this disease.

Comparison of routine field epidemiology and whole genome sequencing to identify tuberculosis transmission in a remote setting.

Yukon Territory (YT) is a remote region in northern Canada with ongoing spread of tuberculosis (TB). To explore the utility of whole genome sequencing (WGS) for TB surveillance and monitoring in a setting with detailed contact tracing and interview data, we used a mixed-methods approach. Our analysis included all culture-confirmed cases in YT (2005-2014) and incorporated data from 24-locus Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTR) genotyping, WGS and contact tracing. We compared field-based (contact investigation (CI) data + MIRU-VNTR) and genomic-based (WGS + MIRU-VNTR + basic case data) investigations to identify the most likely source of each person's TB and assessed the knowledge, attitudes and practices of programme personnel around genotyping and genomics using online, multiple-choice surveys (n = 4) and an in-person group interview (n = 5). Field- and genomics-based approaches agreed for 26 of 32 (81%) cases on likely location of TB acquisition. There was less agreement in the identification of specific source cases (13/22 or 59% of cases). Single-locus MIRU-VNTR variants and limited genetic diversity complicated the analysis. Qualitative data indicated that participants viewed genomic epidemiology as a useful tool to streamline investigations, particularly in differentiating latent TB reactivation from the recent transmission. Based on this, genomic data could be used to enhance CIs, focus resources, target interventions and aid in TB programme evaluation.

Whole genome sequencing for improved understanding of Mycobacterium tuberculosis transmission in a remote circumpolar region.

Few studies have used genomic epidemiology to understand tuberculosis (TB) transmission in rural and remote settings - regions often unique in history, geography and demographics. To improve our understanding of TB transmission dynamics in Yukon Territory (YT), a circumpolar Canadian territory, we conducted a retrospective analysis in which we combined epidemiological data collected through routine contact investigations with clinical and laboratory results. Mycobacterium tuberculosis isolates from all culture-confirmed TB cases in YT (2005-2014) were genotyped using 24-locus Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTR) and compared to each other and to those from the neighbouring province of British Columbia (BC). Whole genome sequencing (WGS) of genotypically clustered isolates revealed three sustained transmission networks within YT, two of which also involved BC isolates. While each network had distinct characteristics, all had at least one individual acting as the probable source of three or more culture-positive cases. Overall, WGS revealed that TB transmission dynamics in YT are distinct from patterns of spread in other, more remote Northern Canadian regions, and that the combination of WGS and epidemiological data can provide actionable information to local public health teams.

Technical characteristics of elite junior men and women race walkers.

AIM: Successful coaching in race walking requires a thorough understanding of the biomechanical principles underlying this unique form of gait. The purpose of this study was to analyze elite male and female junior race walkers and identify key kinematic variables. METHODS: Twenty junior men and 20 junior women were videoed as they competed over 10 km in the 8th European Cup Race Walking. Three-dimensional kinematic data were obtained using motion analysis software (SIMI, Munich). RESULTS: Step length and cadence were correlated with speed in both sexes, and greater step lengths were the kinematic reason for junior men's faster walking speeds. While cadence did not differ between junior men and junior women, there was a difference in proportion of step time spent in contact. There were some differences between genders for upper body joint angles (e.g., elbow) but there were few differences within lower limb joint angles. CONCLUSION: Although some technical aspects (e.g., pelvic and shoulder girdle rotation) appeared undeveloped, it was noteworthy that most athletes achieved full knee extension at initial contact in accordance with the rules. However, in many athletes flight times were evident that might present problems during the transition to the higher standards of senior competition. There was a large range of ability among both sexes and coaches are advised to ensure that technical development continues during the transition to senior competition.

Increase in ST-11 serogroup W Neisseria meningitidis invasive meningococcal disease in Canada, 2016-2018.

BACKGROUND: Many countries have experienced increases in invasive meningococcal disease (IMD) due to a serogroup W Neisseria meningitidis (MenW) strain of the multilocus sequence type (ST)-11 clonal complex (CC). MenW ST-11 was first reported in Ontario, Canada, in 2014. By 2016, this strain caused IMD in five provinces and was responsible for 18.8% of the IMD cases in Canada. OBJECTIVE: To provide an update on invasive MenW disease in Canada including the strain characteristics, specimen source of isolates, age, sex and geographic distribution of cases. METHODS: N. meningitidis from culture-positive IMD cases are routinely submitted to the National Microbiology Laboratory (NML) for serogroup, serotype, serosubtype and sequence type analysis. The data from January 1, 2016 to December 31, 2018 were analyzed by calculating the proportion of IMD cases caused by MenW compared with other serogroups. In addition, trends based on age, sex and geographic distribution of cases and specimen source of isolates were analyzed based on information on specimen requisition forms. RESULTS: Over the 3-year period, 292 individual IMD case isolates were analyzed. The percentage of IMD case isolates typed as MenW more than doubled from 19% (n=15) to 44% (n=51) in 2018 when MenW became the most common serogroup, exceeded the number of MenB, MenC or MenY. In total, 93 MenW case isolates were identified, 91% (n=85) belonged to the ST-11 CC. The increase in MenW affected all age groups (but was most common in those older than 60) and both sexes, and occurred across the country but most prevalent in western Canada. The most common specimen source was blood. CONCLUSION: In 2018, MenW was the most common serogroup for isolates received by the NML from culture-positive IMD cases in Canada. Over 90% of the MenW serogroup isolates belonged to the ST-11 CC. The quadrivalent ACWY meningococcal conjugate vaccine protects against IMD caused by strains in the A, C, W or Y serogroups and therefore may protect against IMD caused by the new MenW ST-11 strain; however, more research is needed. The emergence of variant strains highlight the importance of strain characterization in IMD surveillance and research.

Tuberculosis in the Circumpolar Region, 2006-2012.

SETTING: The northern circumpolar jurisdictions Canada (Northwest Territories, Nunavik, Nunavut, Yukon), Finland, Greenland, Norway, Russian Federation (Arkhangelsk), Sweden and the United States (Alaska). OBJECTIVE: To describe and compare demographic, clinical and laboratory characteristics, including drug resistance and treatment completion, of tuberculosis (TB) cases in the northern circumpolar populations. DESIGN: Descriptive analysis of all active TB cases reported from 2006 to 2012 for incidence rate (IR), age and sex distribution, sputum smear and diagnostic site characteristics, drug resistance and treatment completion rates. RESULTS: The annual IR of TB disease ranged from a low of 4.3 per 100 000 population in Northern Sweden to a high of 199.5/100 000 in Nunavik, QC, Canada. For all jurisdictions, IR was higher for males than for females. Yukon had the highest proportion of new cases compared with retreatment cases (96.6%). Alaska reported the highest percentage of laboratory-confirmed cases (87.4%). Smear-positive pulmonary cases ranged from 25.8% to 65.2%. Multidrug-resistant cases ranged from 0% (Northern Canada) to 46.3% (Arkhangelsk). Treatment outcome data, available up to 2011, demonstrated >80% treatment completion for four of the 10 jurisdictions. CONCLUSION: TB remains a serious public health issue in the circumpolar regions. Surveillance data contribute toward a better understanding and improved control of TB in the north.

The Posterodorsal Medial Amygdala Regulates the Timing of Puberty Onset in Female Rats.

Obesity is the major risk factor for early puberty, but emerging evidence indicates other factors including psychosocial stress. One key brain region notable for its role in controlling calorie intake, stress, and behavior is the amygdala. Early studies involving amygdala lesions that included the medial nucleus advanced puberty in rats. More recently it was shown that a critical site for lesion-induced hyperphagia and obesity is the posterodorsal subnucleus of the medial amygdala (MePD), which may explain the advancement of puberty. Glutamatergic activity also increases in the MePD during puberty without a corresponding γ-aminobutyric acid (GABA)ergic change, suggesting an overall activation of this brain region. In the present study, we report that neurotoxic lesioning of the MePD advances puberty and increases weight gain in female rats fed a normal diet. However, MePD lesioned rats fed a 25% nonnutritive bulk diet also showed the dramatic advancement of puberty but without the increase in body weight. In both dietary groups, MePD lesions resulted in an increase in socialization and a decrease in play fighting behavior. Chronic GABAA receptor antagonism in the MePD from postnatal day 21 for 14 days also advanced puberty, increased socialization, and decreased play fighting without altering body weight, whereas glutamate receptor antagonism delayed puberty and decreased socialization without affecting play fighting. In conclusion, our results suggest the MePD regulates the timing of puberty via a novel mechanism independent of change in body weight and caloric intake. MePD glutamatergic systems advance the timing of puberty whereas local GABAergic activation results in a delay.

Involving consumers in designing, conducting, and interpreting randomised controlled trials: questionnaire survey.

OBJECTIVE: To assess the extent to which consumers are involved in the work of clinical trial coordinating centres in the United Kingdom and the nature of consumers' involvement in randomised trials coordinated by these centres. DESIGN: National surveys using structured questionnaires with some open ended sections. SETTING: 103 clinical trial coordinating centres in the United Kingdom identified through a database assembled in 1997 by the NHS clinical trials adviser. PARTICIPANTS: Named contacts at 62 coordinating centres and investigators in 60 trials that were identified as involving consumers. MAIN OUTCOME MEASURES: Number of coordinating centres and number of trials in which consumers were involved and the nature of consumers' involvement. RESULTS: Of the 62 eligible centres, 23 reported that consumers had already been involved in their work, and most respondents were positive about this involvement. 17 centres planned to involve consumers. 15 centres had no plans to involve consumers, but only four of these considered such involvement irrelevant. Responses from investigators about the 48 individual trials were mostly positive, with respondents commenting that input from consumers had helped refine research questions, improve the quality of patient information, and make the trial more relevant to the needs of patients. CONCLUSIONS: Consumer involvement in the design and conduct of controlled trials seems to be growing and seems to be welcomed by most researchers. Such involvement seems likely to improve the relevance to consumers of the questions addressed and the results obtained in controlled trials.

Home health care.

Home health care, say Kent and Hanley, was originally the purview of nursing. Today, much of home care policy and delivery is determined by cost and reimbursement policies. But is the present policy effective in either delivering services or saving costs? No, say these authors, in a crisp analysis of home care health policies and nursing's part in care delivery in the home setting.

Position paper on social work values: practice with individuals who have developmental disabilities.

This position paper was developed in response to a discussion led by Iris Gordon, president of the Social Work Division of the American Association on Mental Retardation (AAMR) at the 1991 annual meeting on the importance of social work values and the need for clarification in other divisions of the AAMR. The role of social workers and the importance of social work values in the field of developmental disabilities were discussed.

Developmental expression of plant snRNAs.

Although the number of plant U1, U2, U4 and U5 small nuclear RNA (snRNA) variants sequenced has steadily increased over the past few years, the function of these variants in plant splicing is still not understood. In an effort to elucidate the function of plant snRNA variants, we have examined the expression of U1-U6 snRNA variants during pea seedling development. In contrast to mammalian nuclei which express a single, abundant form of each snRNA, pea nuclei express several equally abundant variants of the same snRNA. Comparison of the snRNAs in pea seeds and seedlings has revealed that four (U1, U2, U4, U5) of the five snRNAs required for pre-mRNA splicing have differentially- and developmentally-regulated forms detectable on Northerns. Only U6 snRNA, which fractionates as a single species on Northerns, appears to be constitutively expressed. Switches in the expression of the pea U1, U2 and U4 snRNAs occur at three distinct stages in development: seed maturation, seed germination and seedling maturation. Surprisingly, the snRNA profiles of mature desiccated seeds and mature leaf tissues are nearly identical and different from developing seeds and seedlings suggesting that switches in the snRNA population occur at transitions between active and inactive transcription. Sequence analysis and differential hybridization of the U1 snRNA variants has demonstrated that some of the developmentally-regulated forms represent sequence variants. We conclude that select subsets of pea snRNAs accumulate at particular stages during plant development.

cDNA cloning of U1, U2, U4 and U5 snRNA families expressed in pea nuclei.

Differences observed between plant and animal pre-mRNA splicing may be the result of primary or secondary structure differences in small nuclear RNAs (snRNAs). A cDNA library of pea snRNAs was constructed from anti-trimethylguanosine (m3(2,2,7)G immunoprecipitated pea nuclear RNA. The cDNA library was screened using oligo-deoxyribonucleotide probes specific for the U1, U2, U4 and U5 snRNAs. cDNA clones representing U1, U2, U4 and U5 snRNAs expressed in seedling tissue have been isolated and sequenced. Comparison of the pea snRNA variants with other organisms suggest that functionally important primary sequences are conserved phylogenetically even though the overall sequences have diverged substantially. Structural variations in U1 snRNA occur in regions required for U1-specific protein binding. In light of this sequence analysis, it is clear that the dicot snRNA variants do not differ in sequences implicated in RNA:RNA interactions with pre-mRNA. Instead, sequence differences occur in regions implicated in the binding of small ribonucleoproteins (snRNPs) to snRNAs and may result in the formation of unique snRNP particles.

Plant intron sequences: evidence for distinct groups of introns.

In vivo and in vitro RNA splicing experiments have demonstrated that the intron splicing machineries are not interchangeable in all organisms. These differences have prevented the efficient in vivo expression of monocot genes containing introns in dicot plants and the in vitro excision of some plant introns in HeLa cell in vitro splicing extracts. We have analyzed plant introns for sequence differences which potentially account for the functional splicing differences. Three classes of plant introns can be differentiated by the purine or pyrimidine-richness of sequences upstream from the 3' splice site. The frequency of these three types of introns in monocots and dicots varies significantly. The degree of variability in the 5' and 3' intron boundaries is evaluated for each of these classes in monocots and dicots. The 5' splice site consensus sequences developed for the monocot and dicot introns differ in their ability to base pair with conserved nucleotides present at the 5' end of many U1 snRNAs.

A Structural Comparison of the Acidic Extracellular Polysaccharides from Rhizobium trifolii Mutants Affected in Root Hair Infection.

The structures of the acidic extracellular polysaccharides (EPSs) from several R. trifolii mutants were compared by examining their compositions and their sugar linkages as determined by methylation analysis. These mutant strains were derived from the wild-type R. trifolii ANU843 and were unable to induce normal root hair curling (Hac- phenotype) or nodulation response (Nod- phenotype) in clover plants. These strains included several transposon Tn5-induced Nod-mutants, strain ANU871, which possesses a 40 to 50 kilobase deletion of the resident Sym plasmid, and strain ANU845 which is missing the Sym plasmid (pSym-). Strains ANU845(pSym-) containing either plasmid pRt150 or pBR1AN were also used. The recombinant plasmid pRt150 restores only root hair curling capacity to ANU845 while plasmid pBR1AN (an R. trifolii pSym) restores both root hair curling and nodulation capacity to this strain. Our composition and methylation results show that the EPSs from all these strains have the same glycosyl and pyruvyl linkages. Thus we suggest that neither the nod genes involved in root hair curling nor the entire pSym encodes for the arrangement of glycosyl or pyruvyl residues in these EPSs. Whether or not the nod genes dictate the location of acetyl or beta-hydroxybutyrate substituent groups remains to be determined.