The dawn of repurposing vitamins as potential novel antimicrobial agents: A call for global emergency response amidst AMR crisis.

Amidst, the global pandemic of antimicrobial resistance (AMR), the rate at which AMR increases overwhelms the increased efforts to discover new effective antimicrobials. There is a persistent need for alternative treatment modalities so as to keep up with the pace. AMR is the leading cause of death in the world and its health and economic consequences suggest the urgent need for sustainable interventions. Vitamins have consistently proven to have antimicrobial activity as well as slowing down the AMR rate by influencing the AMR genes even towards extensive multidrug resistant strains. Evidences suggest that the use of some vitamins on their own or in combination with existing antimicrobial agents could be a breakthrough towards combating AMR. This will widen the antimicrobial agents' options in the treatment arena, preserve the antimicrobial agents susceptible to develop resistant so that they can be used in severe infections only, reduce the tension and burden of the AMR crisis significantly and give enough room for development of new antimicrobial agents. Moreover, almost all viral, fungal, parasitic and bacterial resistant strains of concern as listed by World Health Organization have been found to be sensitive to several vitamins either synergistically with other antimicrobials or independently. Considering their widened spectrum of immunomodulatory and antimicrobial effect, some vitamins can further be repositioned as prophylactic antimicrobial agents in clinical situations like in presurgeries prophylaxis so as to avoid unnecessary use of antimicrobials especially antibiotics. Various relevant AMR stakeholders should invest in clinical trials and systematic reviews with available data to enable quick repositioning of some potential vitamins as antimicrobial agents as an emergency rapid response towards AMR Crisis. This includes the preparation of guidelines containing specificity of which vitamin to be used for treatment of which type of infection.

Global increased cesarean section rates and public health implications: A call to action.

Over the years; global caesarian section (CS) rates have significantly increased from around 7% in 1990 to 21% today surpassing the ideal acceptable CS rate which is around 10%-15% according to the WHO. However, currently, not all CS are done for medical reasons with rapidly increasing rate of nonmedically indicated CS and the so-called "caesarian on maternal request." These trends are projected to continue increasing over this current decade where both unmet needs and overuse are expected to coexist with the projected global rate of 29% by 2030. CS reduces both maternal and neonatal morbidity and mortality significantly when it is done under proper indications while at the same time, it can be of harm to the mother and the child when performed contrary. The later exposes both the mother and the baby to a number of unnecessary short and long-term complications and increase the chances of developing different noncommunicable diseases and immune-related conditions among babies later in life. The implications of lowering SC rate will ultimately lower healthcare expenditures. This challenge can be addressed by several ways including provision of intensive public health education regarding public health implications of increased CS rate. Assisted vaginal delivery approaches like the use of vacuum and forceps and other methods should be considered and encouraged during delivery as long as their indications for implementation are met. Conducting frequent external review and audits to the health facilities and providing feedback regarding the rates of CS deliveries can help to keep in check the rising CS trends as well as identifying the settings with unmet surgical needs. Moreover, the public especially expectant mothers during clinic visits and clinicians should be educated and be informed on the WHO recommendations on nonclinical interventions towards reduction of unnecessary CS procedures.

The Influence of Acitretin on Brain Lipidomics in Adolescent Mice-Implications for Pediatric and Adolescent Dermatological Therapy.

Administration of systemic retinoids such as acitretin has not been approved yet for pediatric patients. An adverse event of retinoid-therapy that occurs with lower prevalence in children than in adults is hyperlipidemia. This might be based on the lack of comorbidities in young patients, but must not be neglected. Especially for the development of the human brain up to young adulthood, dysbalance of lipids might be deleterious. Here, we provide for the first time an in-depth analysis of the influence of subchronic acitretin-administration on lipid composition of brain parenchyma of young wild type mice. For comparison and to evaluate the systemic effect of the treatment, liver lipids were analogously investigated. As expected, triglycerides increased in liver as well as in brain and a non-significant increase in cholesterol was observed. However, specifically brain showed an increase in lyso-phosphatidylcholine and carnitine as well as in sphingomyelin. Group analysis of lipid classes revealed no statistical effects, while single species were tissue-dependently changed: effects in brain were in general more subtly as compared to those in liver regarding the mere number of changed lipid species. Thus, while the overall impact of acitretin seems comparably small regarding brain, the change in individual species and their role in brain development and maturation has to be considered.

The life cycle of Puccinia digitariae on Digitaria eriantha and Solanum species in South Africa.

Rust fungi are important plant pathogens and have been extensively studied on crops and other host plants worldwide. This study describes the heterecious life cycle of a rust fungus on Digitaria eriantha (finger grass) and the Solanum species S. lichtensteinii (large yellow bitter apple), S. campylacanthum (bitter apple), and S. melongena (eggplant) in South Africa. Following field observations, inoculation studies involving telial isolates collected from Digitaria plants produced spermogonia and aecia on S. lichtensteinii, S. campylacanthum, and S. melongena. Likewise, inoculation of finger grass with aeciospores collected from the aforementioned Solanum species produced uredinia on D. eriantha. Pennisetum glaucum (pearl millet varieties Milkstar and Okashana, as well as 17 experimental lines) and S. elaeagnifolium (silverleaf nightshade or bitter apple) were resistant to the rust isolates. Morphological descriptions and molecular phylogenetic data confirmed the identity of the rust on Digitaria as P. digitariae, herein reinstated as a species and closely related to P. penicillariae the pearl millet rust, also reinstated. Puccinia digitariae has a macrocyclic, heterecious life cycle in which teliospores overwinter on dormant D. eriantha plants. Aecia sporulate on species of Solanum during spring and early summer to provide inocula that infect new growth of Digitaria.

Shotgun lipidomics of liver and brain tissue of Alzheimer's disease model mice treated with acitretin.

Alzheimer's disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-ß (Aß). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aß-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

Methylxanthines and Neurodegenerative Diseases: An Update.

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson's disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.

Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells.

Methylxanthines are a group of substances derived from the purine base xanthine with a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1 and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate the transcriptional regulation of 83 genes linked to Alzheimer's disease in the presence of five methylxanthines, including the most prominent naturally occurring methylxanthines-caffeine, theophylline and theobromine-and the synthetic methylxanthines pentoxifylline and propentofylline. Methylxanthine-regulated genes were found in pathways involved in processes including oxidative stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene regulation for caffeine compared to the other methylxanthines, which was further substantiated by multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the replacement of single methylxanthines by others could result in unexpected effects, which could not be anticipated by the comparison to other substances in this substance class.

Regulatory feedback cycle of the insulin-degrading enzyme and the amyloid precursor protein intracellular domain: Implications for Alzheimer's disease.

One of the major pathological hallmarks of Alzheimer´s disease (AD) is an accumulation of amyloid-ß (Aß) in brain tissue leading to formation of toxic oligomers and senile plaques. Under physiological conditions, a tightly balanced equilibrium between Aß-production and -degradation is necessary to prevent pathological Aß-accumulation. Here, we investigate the molecular mechanism how insulin-degrading enzyme (IDE), one of the major Aß-degrading enzymes, is regulated and how amyloid precursor protein (APP) processing and Aß-degradation is linked in a regulatory cycle to achieve this balance. In absence of Aß-production caused by APP or Presenilin deficiency, IDE-mediated Aß-degradation was decreased, accompanied by a decreased IDE activity, protein level, and expression. Similar results were obtained in cells only expressing a truncated APP, lacking the APP intracellular domain (AICD) suggesting that AICD promotes IDE expression. In return, APP overexpression mediated an increased IDE expression, comparable results were obtained with cells overexpressing C50, a truncated APP representing AICD. Beside these genetic approaches, also AICD peptide incubation and pharmacological inhibition of the γ-secretase preventing AICD production regulated IDE expression and promoter activity. By utilizing CRISPR/Cas9 APP and Presenilin knockout SH-SY5Y cells results were confirmed in a second cell line in addition to mouse embryonic fibroblasts. In vivo, IDE expression was decreased in mouse brains devoid of APP or AICD, which was in line with a significant correlation of APP expression level and IDE expression in human postmortem AD brains. Our results show a tight link between Aß-production and Aß-degradation forming a regulatory cycle in which AICD promotes Aß-degradation via IDE and IDE itself limits its own production by degrading AICD.

[Detection and treatment of familial hypercholesterolaemia; the earlier, the better?] / Opsporing en behandeling van erfelijk hoog cholesterol.

A recent Dutch study in patients with familial hypercholesterolaemia (FH), suggests that long-term statin treatment initiated at childhood reduces the risk for cardiovascular events in adulthood. None of the patients developed rhabdomyolysis or other serious adverse effects. Early detection of FH is crucial for early treatment initiation. However, the Dutch cascade screening program ended at the end of 2013, at which point approximately 40,000 FH patients had not yet been identified. In order to trace this cohort, in 2014 the 'LEEFH' foundation (National Expertise Centre for Genetic Testing for Familial Cardiovascular Diseases) was set up. Family members of index patients are no longer actively approached to be tested, and as a result the number of detected family members has decreased significantly. These study findings underline the importance of actively screening the family members of index patients, including children and adolescents.

Site fragmentation, hominin mobility and LCT variability reflected in the early Acheulean record of the Okote Member, at Koobi Fora, Kenya.

From its initial appearance at ∼1.7 Ma, the Acheulean was prevalent through a vast chronological span of hominin behavioural evolution that lasted nearly 1.5 million years. The origins and production patterns of large bifacial cutting tools ('LCTs') - the marker of the Acheulean techno-complex - and the systematic changes in this behaviour through time are gaining increasing interest in paleoanthropology. Here we provide a synthesis of early Acheulean LCT variation in a landscape context by analysing assemblages from four different quasi-contemporaneous (∼1.4 Ma) sites from the Koobi Fora Formation. We characterize this variation using both 3D geometric morphometric and descriptive approaches. The expansive lateral exposures of fluvial and lacustrine sediments, as well as the associated tephrostratigraphy of the Koobi Fora Formation provide the landscape context that enables these comparative analyses. Our study demonstrates that when multiple contemporaneous early Acheulean localities are analysed together, a broader picture of LCT variability is elucidated. Four sites at Koobi Fora appear to represent a single system of lithic economy, characterized by a discrete trajectory of changes in LCT size and shape. These sites have ranges of LCT forms which appear to represent different but overlapping stages on a single reduction trajectory. Certain sites exhibit the full reduction trajectory while others exhibit only fragments of this trajectory. Other inter-site lithic proxies further complement these patterns in LCT variability. We explore patterns of site function, mobility and hominin landscape use, all of which may be suggestive of a depth of planning in early Acheulean hominins wherein technological activities were undertaken in substantial anticipation of future needs.

Recent developments in genetics and medically assisted reproduction: from research to clinical applications.

Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.

Recent developments in genetics and medically-assisted reproduction: from research to clinical applications†‡.

Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively-parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.

What is Still Bay? Human biogeography and bifacial point variability.

'Still Bay' is the name given to a cultural phase within the southern African Middle Stone Age, which remains critical to our understanding of modern human behavioural evolution. Although represented in only a handful of sites, the Still Bay is widespread geographically and, at certain localities, persisted over a substantial period of time. Many studies have focused on tracing the temporal range and geographic reach of the Still Bay, as well as inferring degrees of early modern human demographic connectedness from these parameters. Variation within the Still Bay, relative to the accuracy with which it can be identified, has received considerably less attention. However, demographic models based on the spread of the Still Bay in space and time hinge on the reliability with which it can be recognized in the archaeological record. Here we document patterns of bifacial point shape and size variation in some key Still Bay assemblages, and analyse these patterns using the statistical shape analysis tools of geometric morphometrics. Morphological variation appears to be geographically structured and is driven by the spatial separation between north-eastern and south-western clusters of sites. We argue that allometric variation is labile and reflects environmentally driven differences in point reduction, whereas shape differences unrelated to size more closely reflect technological and cultural fragmentation. Our results suggest that the biogeographic structure of Middle Stone Age populations was complex during the period associated with the Still Bay, and provide little support for heightened levels of cultural interconnectedness between distantly separated groups at this time. We briefly discuss the implications of our findings for tracing classic techno-traditions in the Middle Stone Age record of southern Africa, and for inferring underpinning population dynamics from these patterns.

Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome.

BACKGROUND: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. METHODS: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. RESULTS: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case-control status and genomic kinship coefficient. CONCLUSIONS: In this case-control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents.

A genetic diagnosis of maturity-onset diabetes of the young (MODY): experiences of patients and family members.

AIMS: Genetic testing for maturity-onset diabetes of the young (MODY) facilitates a correct diagnosis, enabling treatment optimization and allowing monitoring of asymptomatic family members. To date, the majority of people with MODY remain undiagnosed. To identify patients' needs and areas for improving care, this study explores the experiences of patients and family members who have been genetically tested for MODY. METHODS: Fourteen semi-structured interviews with patients and the parents of patients, and symptomatic and asymptomatic family members were conducted. Atlas.ti was used for thematic analysis. RESULTS: Most people with MODY were initially misdiagnosed with Type 1 or Type 2 diabetes; they had been seeking for the correct diagnosis for a long time. Reasons for having a genetic test included reassurance, removing the uncertainty of developing diabetes (in asymptomatic family members) and informing relatives. Reasons against testing were the fear of genetic discrimination and not having symptoms. Often a positive genetic test result did not come as a surprise. Both patients and family members were satisfied with the decision to get tested because it enabled them to adjust their lifestyle and treatment accordingly. All participants experienced a lack of knowledge of MODY among healthcare professionals, in their social environment and in patient organizations. Additionally, problems with the reimbursement of medical expenses were reported. CONCLUSIONS: Patients and family members are generally positive about genetic testing for MODY. More education of healthcare professionals and attention on the part of diabetes organizations is needed to increase awareness and optimize care and support for people with MODY.

Neonatal diagnosis of Down syndrome in The Netherlands: suspicion and communication with parents.

OBJECTIVES: To analyse which dysmorphic features are most recognised in newborns with Down syndrome (DS). Furthermore to evaluate the communication techniques used by clinicians to inform parents about the postnatal diagnosis and compare these to current best practice guidelines. STUDY DESIGN: Prospective study of a birth cohort of newborns with DS born between 1 January 2003 and 31 December 2006 registered by the Dutch Paediatric Surveillance Unit (DPSU). RESULTS: A total of 586 children with trisomy 21 were analysed. Most recognised dysmorphic features in DS newborns were 'upslanted palpebral fissures' (74.1%; n = 426), 'hypotonia' (73.7%; n = 424) and 'epicanthic folds' (68.5%; n = 394). The majority of parents were informed about the suspected diagnosis on the day of birth (76.5%; n = 390). Hospital deliveries had a significantly earlier suspected diagnosis (mean age 3-4 days) compared with home deliveries (mean age 7 days) (P < 0.05). In 10% (n = 44), paediatricians described dissatisfaction with the first conversation with parents. In 88.9% (n = 499) parents were both present when the diagnosis was told, however the child was not present during the conversation in 51.3% (n = 288). In 10.8% (n = 61) parents were not informed about local parent support groups or community resources. CONCLUSION: DS is still often diagnosed after birth, usually on the first day of postnatal life. Most identified clinical features were upslanted palpebral fissures, epicanthic folds and hypotonia. Special attention for recognition of all present clinical features is needed for early diagnosis. Appropriate communication with the parents of the message that their child has DS can be difficult. Guidelines can help to make counselling easier and more effective, which in turn may increase parental satisfaction. Not all recommendations for the first conversation with parents were fully implemented in Dutch clinical practice.

Informed consent for exome sequencing in diagnostics: exploring first experiences and views of professionals and patients.

Next-generation sequencing is increasingly being chosen as a diagnostic tool for cases of expected genetic, but unresolved origin. The consequential increased need for decisions on disclosure of unsolicited findings poses a challenge for the informed consent procedure. This study explored the first experiences with, and needs for, the informed consent procedure in diagnostic exome sequencing, with the stakeholders involved. Semi-structured interviews were conducted with 11 professional experts and one professional gave a written response. Furthermore, the counseling process was observed in three cases where exome sequencing was offered, followed by interviews with the patient (representative) and the genetic counselor. The respondents not only preferred an opt-out for unsolicited findings but also identified many challenges and therefore more experiences with exome sequencing was considered needed. Context-dependent decision-making was observed and an Advisory Board for unsolicited findings was considered helpful while doubts were raised about the feasibility and the possibility of undermining patients' autonomy. Finally, respondents brought up the complexity of information provision, and division of responsibilities between clinicians and the lab. These challenges and needs, raised by stakeholders involved, provide more insight in the next steps needed for an optimal informed consent procedure for exome sequencing in diagnostics.