Hybridization and reticulate evolution in Diphasiastrum (flat-branched clubmosses, Lycopodiaceae) - New data from the island of Taiwan and Vietnam.

In the species groups related to Diphasiastrum multispicatum and D. veitchii, hybridization was investigated in samples from northern and southern Vietnam and the island of Taiwan, including available herbarium specimens from southeast Asia. The accessions were analyzed using flow cytometry (living material only), Sanger sequencing and multiplexed inter-simple sequence repeat genotyping by sequencing. We detected two cases of ancient hybridization involving different combinations of parental species; both led via subsequent duplication to tetraploid taxa. A cross D. multispicatum × D. veitchii from Malaysia represents D. wightianum, a tetraploid taxon according to reported DNA content measurements of dried material (genome formulas MM, VV and MMVV, respectively). The second case involves D. veitchii and an unknown diploid parent (genome formula XX). Three hybridogenous taxa (genome formulas VVX, VVXX, VVVX) were discernable by a combination of flow cytometry and molecular data. Taxon I (VVX, three clones found on Taiwan island) is apparently triploid. Taxon II represents another genetically diverse and sexual tetraploid species (VVXX) and can be assigned to D. yueshanense, described from Taiwan island but occurring as well in mainland China and Vietnam. Taxon III is as well most likely tetraploid (VVVX) and represented by at least one, more likely two, clones from Taiwan island. Taxa I and III are presumably asexual and new to science. Two independently inherited nuclear markers recombine only within, not between these hybrids, pointing towards reproductive isolation. We present an evolutionary scheme which explains the origin of the hybrids and the evolution of new and fully sexual species by hybridization and subsequent allopolyploidization in flat-branched clubmosses.

Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals.

BACKGROUND: While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. METHODS: We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. RESULTS: 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. CONCLUSIONS: The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term "real world" register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

[The New WHO Guidelines for Rapid Diagnostics and Treatment of Drug-Resistant Tuberculosis Commented for Germany, Austria and Switzerland]. / Die neuen WHO-Empfehlungen für schnelle Diagnostik und Therapie resistenter Tuberkulose in Deutschland, Österreich und der Schweiz.

The increasing evidence has made it necessary to change international recommendations for the diagnosis and treatment of resistant tuberculosis repeatedly in the recent years. This year, the WHO has published comprehensive recommendations that take into account these developments. The current German tuberculosis guideline was published in 2017 with differing recommendations in some areas. Here the new WHO recommendations of 2020 for rapid diagnosis and therapy of resistant tuberculosis are summarized and the relevant differences are commented for Germany, Austria and Switzerland. A complete re-evaluation of the literature is currently taking place by updating the German-language AWMF 2k guidelines.

Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential.

Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1R) in the VTA renders morphine non-rewarding. Complementing our genetic approach, we demonstrate utility of a bivalent pharmacophore with dual activity as a µ/δ opioid agonist and NK1R antagonist in inhibiting nociception in an animal model of acute pain while lacking any positive reinforcement. These data indicate that dual targeting of the dopaminergic reward circuitry and pain pathways with a multifunctional opioid agonist-NK1R antagonist may be an efficacious strategy in developing future analgesics that lack abuse potential.

A systematic review of the quality and scope of economic evaluations in child oral health research.

BACKGROUND: Economic evaluations provide policy makers with information to facilitate efficient resource allocation. To date, the quality and scope of economic evaluations in the field of child oral health has not been evaluated. Furthermore, whilst the involvement of children in research has been actively encouraged in recent years, the success of this movement in dental health economics has not yet been explored. This review aimed to determine the quality and scope of published economic evaluations applied to children's oral health and to consider the extent of children's involvement. METHODS: The following databases were searched: CINAHL, Cochrane Library, Econlit, EThOS, MEDLINE, NHS EED, OpenGrey, Scopus, Web of Science. Full economic evaluations, relating to any aspect of child oral health, published after 1997 were included and appraised against the Drummond checklist and the Consolidated Health Economic Evaluation Reporting Standards by a team of four calibrated reviewers. Data were also extracted regarding children's involvement and the outcome measures used. RESULTS: Two thousand seven hundred fifteen studies were identified, of which 46 met the inclusion criteria. The majority (n = 38, 82%) were cost-effectiveness studies, with most focusing on the prevention or management of dental caries (n = 42, 91%). One study quantified outcomes in Quality Adjusted Life Years (QALYs), and one study utilised a child-reported outcome measure. The mean percentage of applicable Drummond checklist criteria met by the studies in this review was 48% (median = 50%, range = 0-100%) with key methodological weaknesses noted in relation to discounting of costs and outcomes. The mean percentage of applicable CHEERS criteria met by each study was 77% (median = 83%, range = 33-100%), with limited reporting of conflicts of interest. Children's engagement was largely overlooked. CONCLUSIONS: There is a paucity of high-quality economic evaluations in the field of child oral health. This deficiency could be addressed through the endorsement of standardised economic evaluation guidelines by dental journals. The development of a child-centred utility measure for use in paediatric oral health would enable researchers to quantify outcomes in terms of quality adjusted life years (QALYs) whilst promoting child-centred research.

[Migration and Tuberculosis]. / Migration und Tuberkulose.

The majority of the people suffering from tuberculosis in Germany are migrants. The treatment of this demographic still presents certain challenges. Only up to a quarter to a fifth of tuberculosis cases in migrants is being diagnosed by the screening methods that were implemented by The German Protection against Infection Act (Infektionsschutzgesetz, IfSG). Reactivation of latent tuberculosis is the most common cause for tuberculosis in migrants. Easy access to health care is vital for the testing and treatment of latent tuberculosis in people with a high risk of reactivation. The level of infection risk, comorbidities and presentation of disease vary depending on the country of origin. Especially during migration people are more susceptible to somatic and mental maladies. Extrapulmonary tuberculosis is frequent in migrants and requires specific diagnostic approaches. Where risk factors for a multi-drug-resistant tuberculosis are present, this condition has to be actively excluded. To facilitate diagnosis and therapy of tuberculosis in migrants a high level of trust has to be established in the doctor-patient relationship. Therefore and despite of cultural and linguistic differences empathy and time are key. Patients need to be encouraged to complete their treatment rather than terminate it prematurely. To that end comorbidities have also to be diagnosed and treated, social and legal aspects have to be considered.

[Standard therapy of tuberculosis]. / Standardtherapie der Tuberkulose.

Based on the results of studies from the 1960s-1980s the current four drug combination therapy was established as standard or short course tuberculosis therapy worldwide. The regional epidemiology and the often unique conditions within a national health system create the need for specific adjustments. Over the last years these were realized by the German central committee against tuberculosis (DZK) in the recommendations for tuberculosis therapy. Because of the recent development of migration into Germany from countries with higher tuberculosis incidences an increase in tuberculosis cases is to be expected. The expected increase in tuberculosis cases will lead to more contact with tuberculosis patients even in the outpatient setting. New S2k guidelines guided by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) for the treatment of tuberculosis for children and adults are under development. Before the release of the comprehensive guidelines, practical evidence for the diagnosis and treatment of uncomplicated tuberculosis is summarized in this document to meet the challenges of the recent developments.

[New Drugs for the Treatment of Multidrug-resistant Tuberculosis (MDR-TB)]. / Kurze Übersicht über neue Medikamente zur Therapie der multiresistenten Tuberkulose.

This article summarizes the state of development of new drugs for the treatment of multidrug-resistant tuberculosis. We focused on delamanid, bedaquiline, pretomanid, SQ 109 and sutezolid.

[Resistance to second-line drugs in migrants with multidrug-resistant tuberculosis in the Berlin region]. / Resistenzen gegen Zweitlinienmedikamente bei Migranten mit multiresistenter Tuberkulose in der Region Berlin.

The empiric therapy of multidrug-resistant (MDR) tuberculosis (TB) after rapid molecular testing is rendered difficult by an often several weeks-long period of uncertainty, because results of susceptibility testing for second-line TB drugs are pending. The analysis of regional resistance patterns could lead to a more targeted empiric treatment for migrants depending on their country of origin. The results of the susceptibility testing from 2008 to 2013 of all mycobacteria sent to the Institute of Microbiology, working with the department of Pneumology, Heckeshorn Lung Clinic, Berlin, were reanalysed and tested for regional differences. We found 39 multidrug-resistant Mycobacterium tuberculosis strains among the examined strains. More than half of these strains tested susceptible to the following second line drugs namely, linezolid (97%), clofazimine (95%), cycloserine (95%), capreomycin (90%), p-aminosalicylic acid (82%), moxifloxacin (79%) and amikacin (79%). The proportion of strains susceptible to pyrazinamide (44%), ethambutol (28%), prothionamide (15%), rifabutin (8%) and streptomycin (8%) was lower. The mycobacterial cultures of the Chechen patients (n = 14) showed significantly different susceptibilities to amikacin (57%) and prothionamide (36%) compared to the strains from migrants of other regions. In this study, the regional differences in mycobacterial susceptibility to second line drugs suggest that the initial MDR TB therapy of migrants should be tailored to their country of origin.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Clinical, individual and environmental factors related to children's health-related quality of life following treatment under general anaesthetic for dental caries: a path analysis.

OBJECTIVE: To examine the impact of clinical, individual, and environmental factors on children's oral health-related quality of life (OHRQoL) and overall health-related quality of life (HRQoL) following dental caries management under general anaesthetic (GA). METHODS: Participants comprised 5- to 16-year-old children who were referred to a British Dental Hospital, for the management of their dental caries under GA. The Caries Impacts and Experiences Questionnaire for Children (CARIES-QC) and the Child Health Utility 9D (CHU9D) were used to assess child-reported OHRQoL and HRQoL, respectively, at baseline and 3-months follow up. A theoretical conceptual model, based on the Wilson and Cleary model of HRQOL, was evaluated using path analysis to explore indirect and direct relationships of the clinical, individual, and environmental variables on the quality of life outcomes following treatment. RESULTS: 85 children completed the study. Path analyses revealed that 47% of the variance in OHRQoL scores was accounted for by the variables in the model. There were significant relationships between change in OHRQoL score and treatment type [extraction only vs. combination care (ß = 1.41, p = 0.07)] and number of extractions (ß = 0.46, p < 0.001). A higher number of tooth extractions was associated with poorer OHRQoL and HRQoL following treatment. CONCLUSIONS: Treatment type, via number of extractions, may significantly impact on child OHRQoL and HRQoL following treatment under GA. However, to identify any other factors, that might affect these key outcomes, further enquiry is warranted with a bigger sample.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

The impact of dental caries and its treatment under general anaesthetic on children and their families.

OBJECTIVE: To assess the impact of dental caries and treatment under general anaesthetic (GA) on the everyday lives of children and their families, using child-reported measures of quality of life (QoL) and oral health-related quality of life (OHRQoL). METHOD: Participants, aged 5-16 years old having treatment for dental caries under GA, were recruited from new patient clinics at Charles Clifford Dental Hospital, Sheffield. OHRQoL was measured before and 3-months after treatment using the Caries Impacts and Experiences Questionnaire for Children (CARIES-QC). Overall QoL was measured using the Child Health Utility 9D (CHU9D). Parents/caregivers completed the Family Impact Scale (FIS). RESULTS: Eighty five parent-child dyads completed the study. There was statistically significant improvement in OHRQoL (mean interval score difference in CARIES-QC = 4.43, p < 0.001) and QoL (mean score difference in CHU9D = 2.48, p < 0.001) following treatment, with moderate to large effect sizes. There was statistically significant improvement in FIS scores (mean score difference = 5.48, p = 0.03). CONCLUSIONS: Treatment under GA was associated with improvement in QoL and OHRQoL as reported by children, and reduced impacts on the family. This work highlights the importance of GA services in reducing the caries-related impacts experienced by children. Further work is needed investigate the impact of clinical, environmental and individual factors.

Electroconvulsive therapy is equally effective in unipolar and bipolar depression.

OBJECTIVE: To determine the relative efficacy of electroconvulsive therapy (ECT) in the treatment of bipolar (BP) and unipolar (UP) depressive illness and clarify its role in BP depression. METHOD: Patients referred for ECT with both UP and BP depressions. [classified by Structured Clinical Interview for DSM (SCID-I) criteria for history of mania] were included in a multi-site collaborative, double-masked, randomized controlled trial of three electrode placements - right unilateral, bifrontal or bitemporal - in a permutated block randomization scheme. RESULTS: Of 220 patients, 170 patients (77.3%) were classified as UP and 50 (22.7%) as BP depression in the intent-to-treat sample. The remission and response rates and numbers of ECT for both groups were equivalent. CONCLUSION: Both UP and BP depressions remit with ECT. Polarity is not a factor in the response rate. In this sample ECT did not precipitate mania in depressed patients. Treatment algorithms for UP and BP depression warrant re-evaluation.

Drosophila melanogaster and worker honeybees (Apis mellifera) do not require olfaction to be susceptible to honeybee queen mandibular pheromone.

Eusociality is characterised by the reproductive division of labour; a dominant female (queen) or females are responsible for the majority of reproduction, and subordinate females are reproductively constrained. Reproductive constraint can be due to behavioural aggression and/or chemical cues, so-called queen pheromones, produced by the dominant females. In the honeybee, Apis mellifera, this repressive queen pheromone is queen mandibular pheromone (QMP). The mechanism by which honeybee workers are susceptible to QMP is not yet completely understood, however it is thought to be through olfaction via the antennae and/or gustation via trophallaxis. We have investigated whether olfaction is key to sensing of QMP, using both Drosophila melanogaster- a tractable non-eusocial insect which is also reproductively repressed by QMP- and the target species, A. mellifera worker honeybees. D. melanogaster are still capable of sensing and responding to QMP without their antenna and maxillary palps, and therefore without olfactory receptors. When worker honeybees were exposed to QMP but unable to physically interact with it, therefore required to use olfaction, they were similarly not reproductively repressed. Combined, these findings support either a non-olfactory based mechanism for the repression of reproduction via QMP, or redundancy via non-olfactory mechanisms in both D. melanogaster and A. mellifera. This study furthers our understanding of how species are susceptible to QMP, and provides insight into the mechanisms governing QMP responsiveness in these diverse species.