Consumer Safety Considerations of Skin and Oral Microbiome Perturbation.

Microbiomes associated with human skin and the oral cavity are uniquely exposed to personal care regimes. Changes in the composition and activities of the microbial communities in these environments can be utilized to promote consumer health benefits, for example, by reducing the numbers, composition, or activities of microbes implicated in conditions such as acne, axillary odor, dandruff, and oral diseases. It is, however, important to ensure that innovative approaches for microbiome manipulation do not unsafely disrupt the microbiome or compromise health, and where major changes in the composition or activities of the microbiome may occur, these require evaluation to ensure that critical biological functions are unaffected. This article is based on a 2-day workshop held at SEAC Unilever, Sharnbrook, United Kingdom, involving 31 specialists in microbial risk assessment, skin and oral microbiome research, microbial ecology, bioinformatics, mathematical modeling, and immunology. The first day focused on understanding the potential implications of skin and oral microbiome perturbation, while approaches to characterize those perturbations were discussed during the second day. This article discusses the factors that the panel recommends be considered for personal care products that target the microbiomes of the skin and the oral cavity.

Metabolic networks of the human gut microbiota.

The human gut microbiota controls factors that relate to human metabolism with a reach far greater than originally expected. Microbial communities and human (or animal) hosts entertain reciprocal exchanges between various inputs that are largely controlled by the host via its genetic make-up, nutrition and lifestyle. The composition of these microbial communities is fundamental to supply metabolic capabilities beyond those encoded in the host genome, and contributes to hormone and cellular signalling that support the dynamic adaptation to changes in food availability, environment and organismal development. Poor functional exchange between the microbial communities and their human host is associated with dysbiosis, metabolic dysfunction and disease. This review examines the biology of the dynamic relationship between the reciprocal metabolic state of the microbiota-host entity in balance with its environment (i.e. in healthy states), the enzymatic and metabolic changes associated with its imbalance in three well-studied diseases states such as obesity, diabetes and atherosclerosis, and the effects of bariatric surgery and exercise.

The role of external carbonic anhydrase in photosynthesis during growth of the marine diatom Chaetoceros muelleri.

Carbon dioxide concentrating mechanisms (CCMs) act to improve the supply of CO2 at the active site of ribulose-1,5-bisphosphate carboxylase/oxygenase. There is substantial evidence that in some microalgal species CCMs involve an external carbonic anhydrase (CAext ) and that CAext activity is induced by low CO2 concentrations in the growth medium. However, much of this work has been conducted on cells adapted to air-equilibrium concentrations of CO2 , rather than to changing CO2 conditions caused by growing microalgal populations. We investigated the role of CAext in inorganic carbon (Ci ) acquisition and photosynthesis at three sampling points during the growth cycle of the cosmopolitan marine diatom Chaetoceros muelleri. We observed that CAext activity increased with decreasing Ci , particularly CO2 , concentration, supporting the idea that CAext is modulated by external CO2 concentration. Additionally, we found that the contribution of CAext activity to carbon acquisition for photosynthesis varies over time, increasing between the first and second sampling points before decreasing at the last sampling point, where external pH was high. Lastly, decreases in maximum quantum yield of photosystem II (Fv /Fm ), chlorophyll, maximum relative electron transport rate, light harvesting efficiency (α) and maximum rates of Ci - saturated photosynthesis (Vmax ) were observed over time. Despite this decrease in photosynthetic capacity an up-regulation of CCM activity, indicated by a decreasing half-saturation constant for CO2 (K0.5 CO2 ), occurred over time. The flexibility of the CCM during the course of growth in C. muelleri may contribute to the reported dominance and persistence of this species in phytoplankton blooms.

'Framed': Terminating the Parenting Rights of Parents with Intellectual Disability in Iceland.

BACKGROUND: The aim was to investigate the role of measured intellectual function in framing parents as 'unfit' in child custody deprivation cases. METHOD: Grounded theory was used to analyse a national sample of custody deprivation cases in Iceland 2002-2014. RESULTS: The terminology used to evaluate and describe the intellectual and developmental status of parents in child deprivation custody cases served as a device to define and shape the 'unfit parent'. Intellect itself, whether as low, average or even above average at times acts as a master narrative which informs and explains all manner of perceived parental deficiencies. CONCLUSION: The intellectual and developmental status served as a yardstick of identifying, understanding and interpreting the unfit parent. As a tool to achieve an end, parents were framed in language and culture using underlying belief set to make sense of events and issues.

Contrasting evolutionary patterns of 28S and ITS rRNA genes reveal high intragenomic variation in Cephalenchus (Nematoda): Implications for species delimitation.

Concerted evolution is often assumed to be the evolutionary force driving multi-family genes, including those from ribosomal DNA (rDNA) repeat, to complete homogenization within a species, although cases of non-concerted evolution have been also documented. In this study, sequence variation of 28S and ITS ribosomal RNA (rRNA) genes in the genus Cephalenchus is assessed at three different levels, intragenomic, intraspecific, and interspecific. The findings suggest that not all Cephalenchus species undergo concerted evolution. High levels of intraspecific polymorphism, mostly due to intragenomic variation, are found in Cephalenchus sp1 (BRA-01). Secondary structure analyses of both rRNA genes and across different species show a similar substitution pattern, including mostly compensatory (CBC) and semi-compensatory (SBC) base changes, thus suggesting the functionality of these rRNA copies despite the variation found in some species. This view is also supported by low sequence variation in the 5.8S gene in relation to the flanking ITS-1 and ITS-2 as well as by the existence of conserved motifs in the former gene. It is suggested that potential cross-fertilization in some Cephalenchus species, based on inspection of female reproductive system, might contribute to both intragenomic and intraspecific polymorphism of their rRNA genes. These results reinforce the potential implications of intragenomic and intraspecific genetic diversity on species delimitation, especially in biodiversity studies based solely on metagenetic approaches. Knowledge of sequence variation will be crucial for accurate species diversity estimation using molecular methods.

On Predicting lung cancer subtypes using 'omic' data from tumor and tumor-adjacent histologically-normal tissue.

BACKGROUND: Adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most prevalent histological types among lung cancers. Distinguishing between these subtypes is critically important because they have different implications for prognosis and treatment. Normally, histopathological analyses are used to distinguish between the two, where the tissue samples are collected based on small endoscopic samples or needle aspirations. However, the lack of cell architecture in these small tissue samples hampers the process of distinguishing between the two subtypes. Molecular profiling can also be used to discriminate between the two lung cancer subtypes, on condition that the biopsy is composed of at least 50 % of tumor cells. However, for some cases, the tissue composition of a biopsy might be a mix of tumor and tumor-adjacent histologically normal tissue (TAHN). When this happens, a new biopsy is required, with associated cost, risks and discomfort to the patient. To avoid this problem, we hypothesize that a computational method can distinguish between lung cancer subtypes given tumor and TAHN tissue. METHODS: Using publicly available datasets for gene expression and DNA methylation, we applied four classification tasks, depending on the possible combinations of tumor and TAHN tissue. First, we used a feature selector (ReliefF/Limma) to select relevant variables, which were then used to build a simple naïve Bayes classification model. Then, we evaluated the classification performance of our models by measuring the area under the receiver operating characteristic curve (AUC). Finally, we analyzed the relevance of the selected genes using hierarchical clustering and IPA® software for gene functional analysis. RESULTS: All Bayesian models achieved high classification performance (AUC > 0.94), which were confirmed by hierarchical cluster analysis. From the genes selected, 25 (93 %) were found to be related to cancer (19 were associated with ADC or SCC), confirming the biological relevance of our method. CONCLUSIONS: The results from this study confirm that computational methods using tumor and TAHN tissue can serve as a prognostic tool for lung cancer subtype classification. Our study complements results from other studies where TAHN tissue has been used as prognostic tool for prostate cancer. The clinical implications of this finding could greatly benefit lung cancer patients.

Comparative efficacy of digital cognitive behavioral therapy for insomnia: A systematic review and network meta-analysis.

The comparative efficacy of various approaches of digital cognitive behavioral therapy for insomnia (CBTi) is still unclear. This network meta-analysis explored the comparative efficacy of digital CBTi approaches in adults with insomnia. Four electronic databases were searched from inception to June 27, 2020. Primary outcomes were self-reported total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE), and insomnia symptoms; these were measured using sleep diaries or valid questionnaires. A random-effects network meta-analysis in a frequentist framework was used. Fifty-four randomized controlled trials comprising 11,815 participants were included. Compared with usual care, web-based CBTi with a therapist demonstrated significantly longer TST (mean difference [MD]: 23.19 min, 95% confidence interval [CI]: 18.98-27.39 min), shorter SOL (MD: -18.76 min, 95% CI -24.20 to -13.31 min), lower WASO (MD: -31.40 min, 95% CI: -36.26 to -26.55 min), and greater SE (MD: 10.37%, 95% CI: 8.08%-12.65%). The surface under the cumulative ranking curve indicates that web-based CBTi with therapists is most likely to be ranked the highest among all treatments, and thus, this network meta-analysis suggests that such a treatment is the optimal intervention for improving sleep duration and SE as well as the reductions in SOL and WASO. PROSPERO REGISTRATION NUMBER: CRD42020171134.

Splanchnic vein thrombosis: Clinical manifestations, risk factors, management, and outcomes.

BACKGROUND: Clinical manifestations and optimal management strategies in patients with splanchnic vein thrombosis (SVT) are not well characterized. METHODS: We conducted a retrospective cohort study including all newly diagnosed SVT evaluated between January 2007 and December 2018. Efficacy outcome was thrombosis resolution, and safety outcomes included death and occurrence of bleeding. RESULTS: We included 155 patients with a mean age of 56.2 (18-87). Local risk factors were present in 118 (76.1%) patients and 30 (19.4%) had only systemic/thrombophilia. Local risk factors included abdominal cancers (31%), surgery (20.6%) and liver cirrhosis (19.4%). Thrombophilia screening was conducted in approximately 50% of patients. Factor V Leiden or Prothrombin G20210A mutations were observed in 7.1% of patients whereas 14.4% were JAK2V617F mutation positive. Most common manifestations at onset were abdominal pain (56.1%), whereas 44.6% were incidentally found. Portal vein thrombosis was observed more in primary cases (91.9% vs. 69.5%, p = 0.012). Anticoagulation was used in 93.5% cases. Indefinite anticoagulation was used more frequently in primary SVT (62.2% vs. 41.5%, p = 0.045). Thrombosis resolution and bleeding complications among primary (without local risk factors) and secondary (with local risk factors) SVT were observed in 48.5%, 65%, 8.1%, and 11.9%, respectively with no difference when comparing patients treated with direct oral anticoagulants or warfarin and/or low molecular weight heparin (58% vs. 62%, p = 0.326, 9% vs. 12%, p = 0.518). CONCLUSIONS: In this cohort anticoagulation resulted in partial or complete thrombosis resolution in a significant proportion of patients with an acceptable bleeding risk regardless local risk factors or type of anticoagulant.

A Randomized Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of the Novel Myostatin Inhibitor Apitegromab (SRK-015): A Potential Treatment for Spinal Muscular Atrophy.

INTRODUCTION: Apitegromab (SRK-015) is an anti-promyostatin monoclonal antibody under development to improve motor function in patients with spinal muscular atrophy, a rare neuromuscular disease. This phase 1 double-blind, placebo-controlled study assessed safety, pharmacokinetic parameters, pharmacodynamics (serum latent myostatin), and immunogenicity of single and multiple ascending doses of apitegromab in healthy adult subjects. METHODS: Subjects were administered single intravenous ascending doses of apitegromab of 1, 3, 10, 20, 30 mg/kg or placebo, and multiple intravenous ascending doses of apitegromab of 10, 20, 30 mg/kg or placebo. RESULTS: Following single ascending doses, the pharmacokinetic parameters of apitegromab appeared to be similar across all dose groups, following a biphasic pattern of decline in the concentration-time curve. The mean apparent terminal t1/2 after single intravenous doses of apitegromab ranged from 24 to 31 days across dose groups. Dose-related increases were observed in Cmax following multiple ascending doses. Single and multiple apitegromab doses resulted in dose-dependent and sustained increases in serum latent myostatin, indicating robust target engagement. Apitegromab was safe and well tolerated, on the basis of the adverse event (AE) profile with no clinically meaningful changes in baseline vital signs, electrocardiograms, or clinical laboratory parameters and no anti-drug antibody formation. CONCLUSION: These results support continued investigation of apitegromab for the treatment of patients with milder forms (type 2 and 3) of spinal muscular atrophy.

Child Protection, Disability and Obstetric Violence: Three Case Studies from Iceland.

This contribution is a collective re-analysis of three research projects in Iceland focused on parenting with a disability which draws upon data spanning a twenty-year period. The core purpose of these projects is to understand why parents with primarily intellectual disabilities encounter such difficulties with the child protection system. Our aim with this contribution is to identify, through a longitudinal and comparative framework, why these difficulties persist despite a changing disability rights environment. A case study methodology has been employed highlighting three cases, one from each research project, which focus narrowly on disabled parents' struggles with the child protection system in the context of the maternity ward. The findings, framed in the concept of structural violence, indicate poor working practices on the part of healthcare and child protection, a lack of trust, and that context is still ignored in favour of disability as the explanatory framework for the perceived inadequacies of the parents. We contend that child protection authorities continue to remain out of step with developments in disability and human rights. The contribution concludes to make a case as to why the concept of obstetric violence is a useful framework for criticism and advocacy work in this area.

Epigenetic Therapeutics and Their Impact in Immunotherapy of Lung Cancer.

Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Novel therapeutic developments are critically necessary to improve outcomes for this disease. Aberrant epigenetic change plays an important role in lung cancer development and progression. Therefore, drugs targeting the epigenome are being investigated in the treatment of lung cancer. Monotherapy of epigenetic therapeutics such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have so far not shown any apparent benefit while one of the clinical trials with the combinations of DNMTi and HDACi showed a small positive signal for treating lung cancer. Combinations of DNMTi and HDACi with chemotherapies have some efficacy but are often limited by increased toxicities. Preclinical data and clinical trial results suggest that combining epigenetic therapeutics with targeted therapies might potentially improve outcomes in lung cancer patients. Furthermore, several clinical studies suggest that the HDACi vorinostat could be used as a radiosensitizer in lung cancer patients receiving radiation therapy. Immune checkpoint blockade therapies are revolutionizing lung cancer management. However, only a minority of lung cancer patients experience long-lasting benefits from immunotherapy. The role of epigenetic reprogramming in boosting the effects of immunotherapy is an area of active investigation. Preclinical studies and early clinical trial results support this approach which may improve lung cancer treatment, with potentially prolonged survival and tolerable toxicity. In this review, we discuss the current status of epigenetic therapeutics and their combination with other antineoplastic therapies, including novel immunotherapies, in lung cancer management.

A delayed presentation of bilateral leg compartment syndrome following non-stop dancing.

We present the case of a young man with a 48 h delayed presentation of bilateral lower limb acute compartment syndrome (ACS) affecting the anterior compartments following an extended period of dancing at a music festival. On making the diagnosis of ACS, the patient was immediately taken to theatre for fasciotomies and compartmental decompression. Repeat look fasciotomies revealed further necrosis to the muscles of the anterior compartments bilaterally and, effectively, all the muscle bellies within the anterior compartments were excised. The patient has been left with a significant functional deficit and disability. This case highlights the importance of timely diagnosis of ACS as delay in presentation can impact significantly on subsequent functional outcome and quality of life.

Influence of respiration on cerebrospinal fluid movement using magnetic resonance spin labeling.

BACKGROUND: Magnetic resonance imaging (MRI) cardiac gated phase contrast (PC) cine techniques have non-invasively shown the effect of the cardiac pulse on cerebrospinal fluid (CSF) movement. Echo planar imaging (EPI) has shown CSF movement as influenced by both cardiac pulsation and respiration. Previously, it has not been possible to visualize CSF movement in response to respiration non-invasively. The present study was undertaken to do so. METHODS: The effect of respiration on CSF movement was investigated using a non-contrast time-spatial labeling inversion pulse (Time-SLIP) with balanced steady-state free precession (bSSFP) readout. CSF movement was observed in the intracranial compartment in response to respirations in ten normal volunteers. To elucidate the respiration effect, the acquisition was triggered at the beginning of deep inhalation, deep exhalation and breath holding. RESULTS: By employing this respiration-induced spin labeling bSSFP cine method, we were able to visualize CSF movement induced by respiratory excursions. CSF moved cephalad (16.4 ± 7.7 mm) during deep inhalation and caudad (11.6 ± 3.0 mm) during deep exhalation in the prepontine cisternal area. Small but rapid cephalad (3.0 ± 0.4 mm) and caudad (3.0 ± 0.5 mm) movement was observed in the same region during breath holding and is thought to reflect cardiac pulsations. CONCLUSIONS: The Time-SLIP bSSFP cine technique allows for non-invasive visualization of CSF movement associated with respiration to a degree not previously reported.

Identification of McbR as transcription regulator of aecD and genes involved in methionine and cysteine biosynthesis in Corynebacterium jeikeium K411.

The C-S lyase aecD (MetC) from skin corynebacteria plays an important role in body odour formation by releasing odoriferous sulfanylalkanols from cysteine conjugates in human axilla secretions. The expression of the aecD gene from Corynebacterium jeikeium K411, a strain originally isolated from the human axilla, was down-regulated in cells grown in minimal medium supplemented with methionine. A candidate transcription regulator binding in front of the aecD coding region was detected by DNA affinity chromatography and identified as McbR by peptide mass fingerprinting. A 16-bp McbR-binding site was localized in the mapped promoter region of the aecD gene. The binding of purified McbR protein to the 16-bp sequence motif was demonstrated by DNA band shift assays. Comparative DNA microarray hybridizations and bioinformatic motif searches revealed the gene composition of the McbR regulon from C. jeikeium, including 28 genes that are organized in 16 transcription units. The McbR protein from C. jeikeium K411 directly regulates genes involved in methionine uptake and biosynthesis, in cysteine biosynthesis and sulfate reduction, and in the biosynthesis of amino acids belonging to the aspartate family.

Identification of the sex pheromone of Lutzomyia longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae) from Asunción, Paraguay.

The sand fly Lutzomyia longipalpis is the main vector of Leishmania (L.) infantum (Nicolle), the causative agent of American visceral leishmaniasis (AVL) in the New World. Male Lu. longipalpis have secretory glands which produce sex pheromones in either abdominal tergites 4 or 3 and 4. These glands are sites of sex pheromone production and each pheromone type may represent true sibling species. In Latin America, apart from Lu. pseudolongipalpis Arrivillaga and Feliciangeli from Venezuela, populations of Lu. longipalpis s.l. can be identified by their male-produced sex pheromones: (S)-9-methylgermacrene-B, 3-methyl-alpha-himachalene and the two cembrenes, 1 and 2.In this study, we present the results of a coupled gas chromatography - mass spectrometry analysis of the pheromones of males Lu. longipalpis captured in an endemic area of visceral leishmaniasis in Asunción, Paraguay. Our results show that Lu. longipalpis from this site produce (S)-9-methylgermacrene-B which has also been found in Lu. longipalpis from different areas of Brazil, Colombia and Central America.