Due to the variability of an individual’s prognosis and the variety of treatment options available to breast cancer (BC) patients with brain metastases (BM), establishing the proper therapy is challenging. Since 1997, several prognostic tools for BC patients with BM have been proposed with variable precision in determining the overall survival. The majority of prognostic tools include the performance status, the age at BM diagnosis, the number of BM, the primary tumor phenotype/genotype and the extracranial metastases status as an outcome of systemic therapy efficacy. It is necessary to update the prognostic indices used by physicians as advances in local and systemic treatments develop and change the parameters of survival. Free access to prognostic tools online may increase their routine adoption in clinical practice. Clinical trials on BC patients with BM remains a broad field for the application of prognostic tools.Background: Determining the proper therapy is challenging in breast cancer (BC) patients with brain metastases (BM) due to the variability of an individual’s prognosis and the variety of treatment options available. Several prognostic tools for BC patients with BM have been proposed. Our review summarizes the current knowledge on this topic. Methods: We searched PubMed for prognostic tools concerning BC patients with BM, published from January 1997 (since the Radiation Therapy Oncology Group developed) to December 2021. Our criteria were limited to adults with newly diagnosed BM regardless of the presence or absence of any leptomeningeal metastases. Results: 31 prognostic tools were selected: 13 analyzed mixed cohorts with some BC cases and 18 exclusively analyzed BC prognostic tools. The majority of prognostic tools in BC patients with BM included: the performance status, the age at BM diagnosis, the number of BM (rarely the volume), the primary tumor phenotype/genotype and the extracranial metastasis status as a result of systemic therapy. The prognostic tools differed in their specific cut-off values. Conclusion: Prognostic tools have variable precision in determining the survival of BC patients with BM. Advances in local and systemic treatment significantly affect survival, therefore, it is necessary to update the survival indices used depending on the type and period of treatment. PIK3CA alterations [Brain metastases (BM) are a serious consequence of breast cancer (BC) progression. They occur in up to a half of patients with metastatic human epidermal growth factor receptor 2 (HER2) positive or triple-negative BC and frequently occur in luminal phenotypes with erations ,2,3,4. TCurrently, the treatment of BM in BC patients includes neurosurgery, stereotactic radiotherapy (SRS), whole-brain radiotherapy (WBRT) and systemic therapy  .Due to the variability of an individual’s prognosis and the variety of treatment options available to BC patients with BM, establishing the proper therapy is challenging. A patient’s stratification into prognostic classes includes factors related to the patient and his or her disease(s). Beginning in the 1990s, there was a growing interest in developing prognostic tools to provide accurate prognoses, to guide treatment decision making, provide appropriate and cost-effective care and direct clinical trial design. Several prognostic tools in BC patients with BM have been proposed. Our review summarizes the current knowledge on this topic.The present review compares different prognostic tools based on a systematic literature search on PubMed/MEDLINE. It is limited to adult patients with newly diagnosed BM regardless of the presence or absence of leptomeningeal metastases. The keywords used were “brain metastases/brain metastasis” with “prognostic index” with “breast cancer” or “nomogram” or “prognostic score” and “validation studies” for studies published between January 1997 and December 2021.31 prognostic tools were selected: 13 analyzed mixed cohorts with BC cases and 18 were specific to BC. In 1997, the Radiation Therapy Oncology Group (RTOG) developed the first prognostic score for BM patients by using a Recursive Partitioning Analysis (RPA) strategy . The stu3) and the number of lesions (≥3 vs. 2 vs. 1). The median OS within the 3 SIR groups was 2.9, 7.0 and 31 months.In 2000, Weltman et al.  developeLorenzoni et al.  proposedTo predict the survival of BM patients treated with WBRT, Rades et al.  created Sperduto et al.  analyzedRades et al.  updated Barnholtz-Sloan et al.  developeIn 2012, Yamamoto et al.  proposedLee et al.  establisIn 2021, Sato et al.  developeEGRF and ALK in lung cancer), the LDH level (<200 vs. >300 U/L), and the cumulative tumor volume (<3.5 vs. ≥3.5 cm3). Three risk groups were selected with a significant difference in OS. In the total group of 356 patients, only 38 (10.7%) were BC patients.Zhou et al.  presenteFan et al.  construcIn 2005, Claude et al.  retrospeLe Scodan et al.  analyzedIn 2009, Park et al.  retrospeNieder et al.  retrospeIn 2012, Sperduto et al.  developeIn a prospective study, Niwińska et al.  publisheAhn et al.  publisheIn turn, Marko et al.  proposedLe Scodan et al.  developeRades et al.  construcIn 2014, Ahluwalia et al.  validateYang et al.  developeSubbiach et al.  validateHuang et al.  proposedXiong et al.  establisIn 2020, Sperduto et al.  publisheIn 2020, Weykamp et al.  developeLiu et al.  proposedThree separate groups of scientists ,37,38 cop < 0.001) for the OS according to the prognostic category. Pairwise comparisons of each prognostic index revealed statistically significant differences in survival between prognostic classes, except for the breast-GPA classes I vs. II, BS-BM scores 1 vs. 2 and Le Scodan’s scores I vs. II. There were no significant differences between all prognostic indices concerning the survival predicting ability. Only minor differences were seen using Harrell’s c-index (range 0.60–0.68). The authors concluded that RPA seemed to be the most useful score. RPA performed better than new prognostic indices because it was the most accurate in identifying patients with long (>12 months) and short (<3 months) survival.Ahn et al.  in 2012 Tabouret et al.  in 2014 In 2015, Subbiah et al.  validateCastaneda et al.  in 2015 Further, Laakmann et al.  comparedHuang et al.  in 2018 Znidaric et al.  in 2019 Similarly, in 2019 Zhuang et al.  undertooLee et al.  in 2020 Weycamp et al.  in 2020 Since the first Recursive Partitioning Analysis published in 1997, a series of prognostic tools have been developed in BC patients with newly diagnosed BM to facilitate clinical decision-making and appropriate stratification to local and systemic therapy. This review of prognostic tools illustrates how over time, progress in the understanding of the biology of BC and new effective systemic treatments have influenced the prognosis of patients with BM ,33,34,35The majority of prognostic tools in BC patients with BM include the performance status, the age at BM diagnosis, the number of BM (rarely volume), the primary tumor phenotype/genotype and the ECM status as an outcome of the systemic therapy efficacy  19,20,2,33,34,35On the other hand, the BC phenotype or genotype is a main predictive factor of systemic therapy efficacy and ECM control. However, studies assessing ECM status as a prognostic factor used various definitions. Typically, it was the presence of distant metastases outside the brain or their absence ,30,34,35Advanced TNBC and HER2-positive BC have a higher risk of BM . It is aPredicting the survival of BC patients with BM is difficult; therefore, prognostic tools are crucial in stratifying different patients’ outcomes. However, they are limited by their retrospective nature and may underestimate survival in the modern era with the growing number of effective systemic agents. Furthermore, the prognostic tool developed for single institution cohorts might be biased by institutional practice patterns; therefore, external validation for new prognostic tools are the gold standard and should be obtained whenever possible ,56. Morewww.clinicaltrials.gov; accessed on 25 January 2022).International multidisciplinary recommendations, EANO-ESMO and NCCN, do not recommend prognostic tools in BC patients with BM ,49. The In clinical practice, the decision on the treatment sequence of BC patients with newly diagnosed BM should be made by a multidisciplinary team including a medical oncologist, radiotherapist and neurosurgeon, according to the accepted standard operating procedures (SOP). In the management algorithm, it is crucial to provide supportive care to patients with a poor prognosis and an expected survival of less than 3 months; for example, patients with uncontrolled ECM and/or more than 10 BM where systemic pharmacotherapy and WBRT are mainly used. In turn, for the minority of patients, with small and few lesions (1 to 10) depending on the volume <15 mL), who may experience long-term survival or even cure, several approaches are used in combination   mL, who .The universal, ideal prognostic tool should be simple and easily usable. Electronic access to such indices improves their usefulness in clinical practice, e.g., for the modified updated Breast GPA index . Furthermore, new prognostic tools in BC patients with BM should be used more in clinical trials.Prognostic tools have variable precision in determining the survival of BC patients with BM. Progress in local and systemic treatment significantly affects the parameters of survival. Hence, it is necessary to update the prognostic indices used, depending on the period of treatment. Free access to prognostic tools online may increase the frequency of their use in clinical practice. Clinical trials in BC patients with BM remain a broad field for the application of prognostic tools.


Thereaet al. , Cardeño [etal. ). In a rn etal.  contribuet al.'s[2r = 0.48) than its elasmobranchcatch as reported to FAO (2r = 0.20) underlinesthis erroneous assumption. An example of the dissonance caused by excluding fishing activityis northwestern Australia, where Van Houtan et al. [We fundamentally disagree with the central assumption of the paper that there is a directlink between species distribution and shark fin origin. This assumption relies on fisheriescatch being equal through the distribution of a species, which we know is not true. Fishingeffort that catches sharks is spatially heterogeneous  because et al.'s estimaten et al.  indicaten et al. . Such diet al. [Squalus acanthias—do not occur in the fin trade[The paper's use of DNA data from some markets may be misleading since it assumed that allmarkets contributed equally to the global fin trade. For example, Feitosa et al. collecteet al. , and  having serious inaccuracies. In all flawed cases,the SDMs indicate species occurrence well outside their established geographicaldistributions known from decades of fishery and research data, which are reported in widelyavailable species guides (e.g. [Isurus oxyrinchus) primarily occur inthe open ocean rather than coastal environments, grey reef sharks (Carcharhinus amblyrhynchos) do not occur in the Atlantic Ocean, smalleyehammerhead (Sphyrna tudes) occurs only in eastern SouthAmerica  and great hammerheads (Sphyrnamokarran) are mostly coastal and not present to the latitudinal extent as suggestedby the SDMs. This lack of a validity check against knowndistributions results in the allocation of species to exclusive economic zones (EEZs) inwhich they do not occur and hence erroneous probabilities of contributions to the fin trade.With more than 30% of SDMs having major flaws, the errors introduced to the estimation ofthe probability of fin origin are large. Many of the SDMs used by Van Houtan es e.g. ,11). The. Theet aet al. [et al. [−1 [Alopias pelagicus) and scalloped hammerhead sharks (Sphyrna lewini) and Indo-Pacific origins for silky sharks  [The flaws in the methods used by Van Houtan et al.  mean tha [et al. ). For ex al. [−1 , a level al. [−1 . Their f al. [−1 , and geniformis) ,4. ThesePrionace glauca, bigeye thresherAlopias supercilious and shortfin mako shark, Isurus oxyrinchus, which together account for most (more than 50%)shark fins found in the market samples used to populate SDMs. These are all pelagic speciesand open ocean fisheries should have higher dominance in the origin probabilities. However,this result was not apparent because inaccurate SDMs and omission of relevant fisheries datacreated an unrealistic scenario of global shark fisheries. For example, consideringavailable data on these three species, less than 1000 unprocessed t yr−1  are caught in Australia and the USA [−1 in Brazil [If the authors had considered known locations of global fishing activity, the open oceanwould appear a more likely origin for fins ,15. This the USA , and lesn Brazil . If the n Brazil .The misinterpretations and methodological issues of the paper have resulted ininappropriate management recommendations for nations that are examples of best practiceshark fisheries . Their We do not question the occurrence of coastal shark species in the global fin trade, northat opportunities exist to improve shark conservation within EEZs of numerous countries.However, prioritization of shark conservation efforts across countries and the high seasmust consider the realities of the present distribution of species and fisheries activity,and existing national and international management arrangements.


Galba truncatula eDNA. Fourteen potential G. truncatula habitats on two farms were surveyed over a 9-month period, with eDNA detected using a filter capture, extraction and PCR protocol with data analysed using a generalized estimation equation. The probability of detecting G. truncatula eDNA increased in habitats where snails were visually detected, as temperature increased, and as water pH decreased (P < 0.05). Rainfall was positively associated with eDNA detection in watercourse habitats on farm A, but negatively associated with eDNA detection in watercourse habitats on farm B (P < 0.001), which may be explained by differences in watercourse gradient. This study is the first to identify factors associated with trematode intermediate snail host eDNA detection. These factors should be considered in standardized protocols to evaluate the results of future eDNA surveys.Environmental DNA (eDNA) surveying has potential to become a powerful tool for sustainable parasite control. As trematode parasites require an intermediate snail host that is often aquatic or amphibious to fulfil their lifecycle, water-based eDNA analyses can be used to screen habitats for the presence of snail hosts and identify trematode infection risk areas. The aim of this study was to identify climatic and environmental factors associated with the detection of  Both farms had a history of F. hepatica and/or C. daubneyi infections in livestock. Habitats on both farms were selected for the study based on their physical suitability to harbour G. truncatula snails, with all habitats containing standing or flowing water for periods during the summer months, bare mud surfaces and Juncaceae spp. which are indicator plant species for G. truncatula habitats  whilst temperature data were measured by a LogTag Trix-16 Data Logger . These instruments were located within 1.5 km of each study habitat. Water pH was measured for each sample using an 8100 pH and Temperature Meter Kit .The number of μm micro-glass fibre filters  using an electrical suction pump, Büchner flask and a funnel, as described by Jones et al. . All filters, including blank controls, were homogenized using a sterile pipette tip with each whole filter subjected to DNA extraction via the PowerSoil® kit protocol. PCR targeting a 288 bp strand of the G. truncatula ITS2 gene and gel electrophoresis were used to identify G. truncatula eDNA in extracts as previously described by Jones et al.  model, created in SPSS v.27, where the dependent variable was the presence or absence of G. truncatula eDNA in each sample collected. GEE models account for potential correlations within subject, which occurred in this data set as multiple samples collected across sequential time points were nested within the subject (habitat). GEE can also account for missing data points, which also occurred within this data set as not all habitats had water to sample at all sampling points. The working correlation matrix for data inputted into each GEE model was set as AR1, as the lowest Quasi Likelihood under Independence Model Criterion (QIC) values were associated with models created when this working correlation matrix was specified  were sequentially removed. Main effect variables offered during model creation included habitat type (pasture or watercourse), snail presence, water pH, mean temperature (°C) and rainfall (mm) on sampling day, mean daily temperature and rainfall 3 days prior to sampling, sampling month and proportion of weeks in study period where sampling water was present, as were biologically plausible interaction effect variables. Farm identity was also included as a fixed factor in each model to account for potential differences between G. truncatula snail populations on each farm. The final models were selected via their QIC values .In total, 221 samples were collected across 14 habitats during the study, 48% of which were positive for n Farm B . Of the G. truncatula eDNA presence can be seen in G. truncatula eDNA was increased in samples collected when temperatures were higher (P < 0.001) and when sample water pH was lower (P = 0.047). Samples from habitats where the presence of G. truncatula had been confirmed visually during the study period were significantly associated with G. truncatula eDNA presence (P = 0.006). A significant interaction effect on the number of positive replicates between farm, habitat type and mean 3-day rainfall prior to sampling was also observed . In this interaction effect, mean 3-day rainfall pre-sampling was significantly positively associated with G. truncatula eDNA presence in watercourse habitats on Farm A (P = 0.001). Mean 3-day rainfall prior to sampling was significantly negatively associated with G. truncatula eDNA presence on Farm B (P < 0.001). There was no significant association (P = 0.651) between mean 3-day rainfall prior to sampling and G. truncatula eDNA presence in pasture habitats on Farm A.Results of binary GEE analysis of factors associated with et al., G. truncatula eDNA was detected in 12, although eDNA detection was not consistent across all timepoints. eDNA is present in very small quantities in the environment, especially the eDNA of species that are likely to expel low volumes of DNA and that are present in low densities  and highly acidic conditions, known to have a significant effect on DNA degradation (Strickler et al., G. truncatula snail presence and environment pH, although contradictory findings towards the snail's preference for either a slightly acidic or neutral pH are present in the literature (Urquhart et al., et al., et al., G. truncatula due to their humid conditions. A positive relationship was observed between temperature and eDNA detection in this study, which contradicts the known effect of warmer temperatures in accelerating eDNA degradation (Strickler et al., et al., G. truncatula, it has been shown that general activity, feeding, growth, reproduction rate and lifespan were all significantly greater at 16–22°C compared to 5°C (Hodasi, The probability of detecting eDNA may also be impacted by a habitat's exposure to a range of environmental and climatic conditions. Unlike many other studies, where pH was positively associated with eDNA presence and concentration (Strickler  Hodasi, .et al., et al. (et al. (et al., et al., et al., Galba truncatula snails are able to survive these dry conditions across the summer months before remerging to potentially shed infective cercariae (Dreyfuss et al., The association between pre-sampling rainfall and eDNA detection was variable between habitat type and location in this study. On Farm A, rainfall was positively associated with eDNA detection in watercourse habitats, whilst it was negatively associated with eDNA detection on Farm B in watercourse and pasture habitats. One of the main differences between watercourse habitats on Farm A and Farm B was their gradient , which w, et al. , a heavy (et al.  demonstr et al., . This woet al., et al. (et al., et al., G. truncatula watercourse habitats, which are commonly small slow-moving streams and drainage ditches, eDNA transportation down-stream should be limited. Watercourses are also potential movement corridors for G. truncatula snails, with snails capable of either migrating up stream over 100 m a month in some instances (Rondelaud, et al., G. truncatula migration.Considering the complex nature of the relationship between eDNA detection and rainfall seen in this study, the reliability of eDNA detection as an accurate indication of species presence at a particular sampling site may be questioned, especially in watercourse habitats where eDNA can be transported vast distances with the flow of water (Pont , et al.  demonstret al. (et al. (Schistosoma intermediate snail host B. truncatus. However, increasing replicate numbers and sampled water volume can be challenging. Each replicate adds cost to the protocol (Sengupta et al., et al., Two replicate water samples of 500 mL were collected at each sampling point in this study and increasing number of replicates and the sample volume would likely have increased detection rates in this study. According to Schmidt et al. , the pro (et al.  found thGalba truncatula eDNA was significantly more likely to be detected in habitats where G. truncatula snails were surveyed during the study period; however, the density of snails surveyed at each visit was not a significant factor associated with eDNA detection, although this could be explained by the comparatively unsensitive and variable nature of traditional G. truncatula surveys which may fail to identify snails present in mud, water or thick vegetation. This may also explain why G. truncatula eDNA was detected in habitats where these snails were not discovered via traditional surveying methods during the study period, a similar finding to that of Jones et al. (G. truncatula. Detecting the presence of intermediate snail hosts, even in low-density populations may be vital considering that a small number of snails are capable of shedding thousands of infective trematode stages into the environment (Dreyfuss et al., et al., et al., et al., et al., G. truncatula can inhabit permanent wetlands, spring heads, ponds, streams, ditches and poached soils on pastures in both temperate and arid climates (Dreyfuss et al., s et al. . This woG. truncatula, in small water body habitats over time. These factors should be considered when devising standardized eDNA sampling protocols and data analysis to ensure eDNA surveying goals are robustly met. Future research should build on knowledge gained in this study to use and test site occupancy models for identifying G. truncatula and other intermediate snail hosts in small water body habitats.In summary, this study identifies environmental and climatic factors associated with the detection of the trematode intermediate snail host,


The demand for high data rate transfer and large capacities of traffic is continuously growing as the world witnesses the development of the fifth generation 5G) of wireless communications with the fastest broadband speed yet and low latency . WidesprG of wireThis Special Issue covers various aspects of novel antenna designs for 5G and beyond applications. The featured topic articles in this issue highlight recent advances in designing antenna systems for smartphones, small cells, platform stations, massive MIMO, MM-Wave, front-end, metamaterials, and metasurface applications. In addition, other relevant subjects such as spectral efficiency improvement, K-user MIMO, and multi-mode band-pass filter design are discussed. This Special Issue is a collection of fifteen papers that are briefly explained in the following.Seyyedesfahlan et al.  report oOjaroudi Parchin et al.  propose Ojaroudi Parchin et al.  demonstrSharaf et al.  develope3.Dixit et al.  introducSong et al.  present Hamid et al.  focused Kozlov et al.  present Ferreira-Gomes et al.  demonstrRamírez Arroyave et al.  developeGaya et al.  proposedIqbal et al.  have devLuo et al.  present In their work, Dicandia and Genovesi  focused Yerrapragada and Kelley  propose Sensors journal. We hope that readers will discover new and useful information on antenna design techniques for 5G and beyond applications.We would like to take this opportunity to appreciate and thank all authors for their excellent contributions and the reviewers for their fruitful comments and feedback. Special appreciation is also extended to the editorial board and editorial office of MDPI


The decision-making process regarding management after severe acute brain injury is based on clinical evaluation and depends on the injury etiology as well as radiological and neurophysiological data ,2. GrowiBrain Sciences, entitled “Frontiers in biomarkers of brain injury,” Metallinou et al. [The examination of the specific biomarkers of brain injury is not limited to adult patients. In this Special Issue of u et al.  report ou et al. . Perivenu et al. . Activinu et al. . Metalliu et al.  showed tBrain Sciences, Bagnato et al. [Moreover, growing evidence suggests that acute brain injury is followed by chronic neurodegeneration . Accordio et al.  report oo et al. , and chaBiomarkers may also play a role in the evaluation of cognitive impairments after the occurrence of brain injury. Specifically, traumatic brain injury triggers neuroinflammation, which may affect patients’ long-term outcomes . Malik eBrain Sciences highlight the breadth of the fields in which biomarkers have potential applications regarding brain injury, ranging from infants to adult patients and from traumatic to hypoxic-ischemic and acute to chronic injuries. There are several factors that still limit the routine use of several biomarkers in clinical practice, including high costs and the need for specialized skills and specific equipment. It is expected that these obstacles will be overcome in the next few years for several biomarkers, allowing their introduction into routine clinical practice.These examples from the papers published in this Special Issue of


Bacillus subtilis has served as a model microorganism for many decades. There are a few important reasons why this Gram-positive bacterium became a model organism to study basic cell processes. Firstly, B. subtilis has proven highly amenable to genetic manipulation and has become widely adopted as a model organism for laboratory studies. Secondly, it is considered as the Gram-positive equivalent of Escherichia coli, an extensively studied Gram-negative bacterium, and both microorganisms have served as examples for bacterial cell division studies in the last decades. Thirdly, unlike E. coli, it can form endospores and the sporulation represents the simplest cellular differentiation process. In addition, this bacterium became an exceptional specimen to study motility, chromosome segregation, competence, host system for bacteriophages, transcription regulation, biofilm formation, and B. subtilis is also widely used to produce various enzymes, such as proteases, amylase, etc.Bacillus subtilis as a Model Organism to Study Basic Cell Processes” was to provide a platform to researchers for sharing their new studies on advances in basic cell processes studies in the model organism B. subtilis. The Special Issue includes papers from several leading scientists in the field studying sporulation, biofilm formation, bacteriophages, and transcription in this bacterium and its close relatives. The present Special Issue comprises nine research articles and two reviews.The objective of this Special Issue on “B. subtilis. Transcription of specific genes and production of physiologically relevant proteins is crucial for the adaptation of bacteria to changing environmental conditions. Sudzinová et al. [B. subtilis sigma factor σB as a subunit of RNA polymerase. They concentrated on σB-dependent genes expressed specifically during germination and the outgrowth of spores. They determined the binding motif of a subset of σB regulated genes during these parts of B. subtilis life cycle. Importantly, they also experimentally verified sixteen selected SigB dependant promoters.Two articles were focused on studies of transcription and gene expression regulation in á et al.  determiná et al.  used an B. subtilis. They concentrated on G4 DNA and hairpin-forming motifs and they showed that these non-B DNA-forming structures promote genetic instability and may have spatial and temporal mutagenic effects. Faßhauer et al. [B. subtilis cold shock proteins, CspB and CspD proteins. These proteins belong to the most abundant proteins in the cell and thus it suggesting their possible crucial function. Deletion of either of the genes has no clear effect on phenotype. However, the simultaneous loss of both proteins results in severe growth effects and the appearance of suppressor mutations. Interestingly, the global RNA profile of the double mutant suggests that these proteins are important for transcription elongation and termination.Ermi et al.  studied B. subtilis and related bacteria belong to bacteria that can form a surface-associated multicellular assemblage, so-called biofilms. Dergham et al. [B. subtilis NDmed strain. By using different 15 mutant strains they identified genes important for all biofilm phenotypes. Špacapan et al. [Bacillus velezensis strains and analyzed its impacts on biofilm formation and stable colonization on different plant surfaces which finally enables its activity as an elicitor of induced systemic resistance.The next three articles are focused on different aspects of biofilm formation. m et al.  concentrn et al.  studied n et al.  studied B. subtilis has been especially well known for many decades of studies on sporulation, an important mechanism by which bacteria can survive harsh environmental conditions, and it also represents the simplest cell differentiation process. The spore resistance arises from several protective layers that surround the spore core. In addition to the cortex, a peptidoglycan layer, the coat is the main defense system against the challenges of the environment. More than 80 coat proteins are localized into four distinct morphological layers. Krajčíková et al. [Bacillus subtilis A163 in comparison with laboratory B. subtilis, PY79 strain. They showed extremely high resistance to wet heat compared to spores of laboratory strain. They determined the proteome of vegetative and sporulating cells of both strains A163 and PY79 and the results revealed proteomic differences of the two strains what should help to explain the high heat resistance of B. subtilis A163 spores.á et al.  analyzedB. subtilis and Listeria monocytogenes. The authors focused on several ABC transporters, which are not only required to inactivate or export drugs but are essential for drug sensing, and on ABC transporters, which affect cell wall biosynthesis and remodeling. The second review by Łubkowska et al. [Bacillus group’ bacteria. This review of bacteriophages of thermophiles is an important overview not only of their previously described characteristics but also their roles in many biogeochemical, ecological processes, and biotechnology applications, including emerging bionanotechnology.This Special Issue also includes two review articles. Rismondo and Schulz  provideda et al.  provides


In 2009, rapamycin was reported to increase the lifespan of mice when implemented later in life. This observation resulted in a sea-change in how researchers viewed aging. This was the first evidence that a pharmacological agent could have an impact on aging when administered later in life, i.e., an intervention that did not have to be implemented early in life before the negative impact of aging. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on various diseases, physiological functions, and biochemical processes in mice. In this review, we focus on those areas in which there is strong evidence for rapamycin’s effect on aging and age-related diseases in mice, e.g., lifespan, cardiac disease/function, central nervous system, immune system, and cell senescence. We conclude that it is time that pre-clinical studies be focused on taking rapamycin to the clinic, e.g., as a potential treatment for Alzheimer’s disease. Streptomyces hygroscopicus, which was isolated from soil samples collected from Easter Island by Georges Nogrady in the late 1960s [Streptomyces hygroscopicus produced a compound that would kill fungi, which they named rapamycin after the name of Easter Island, Rapa Nui. The initial interest in rapamycin focused on its antifungal properties. When it was found that rapamycin inhibited the growth of eukaryote cells, research on rapamycin turned to rapamycin’s immunosuppressive and anticancer properties. Rapamycin was approved by the FDA in 1994 to prevent organ rejection in liver transplant patients. In addition to being used as an antirejection drug, rapamycin or its rapalogs are being used today to prevent restenosis after coronary angioplasty, and they are being tested in many clinical trials as antitumor agents, e.g., FDA approved the use of rapamycin in treatment of pancreatic cancer patients in 2011.Rapamycin  is a macrocyclic lactone produced by Science, selected this study as one of the major scientific break-throughs in 2009 , the first discovery in aging to be selected by Science as a break-through. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on aging and age-related diseases, and there have been several reviews describing various aspects of rapamycin on aging [Research in the late 1980s turned to identifying the mechanism by which rapamycin blocked the growth of eukaryote cells. Heitman et al.  discoveron aging . In thisCaenorhabditiselegans, and other groups showed that mutations in TOR increased the lifespan of yeast [Drosophila [The first data suggesting that rapamycin might affect longevity came from studies with invertebrates. In 2003, Vellai et al.  showed tof yeast  and Drososophila . Subsequosophila . Based oosophila  reportedosophila , 9 monthosophila , or 19 mosophila  of age. Three additional points of interest with respect to rapamycin’s longevity affect can be seen from Table Lmna−/−) that mimics Hutchinson-Gilford progeria, Ramos et al. [Lmna−/− mice. Khapre et al. [Bmal1−/− mice because knocking out Bmal1 (a transcription factor that is key to the circadian clock) increased mTORC1 activity and reduced lifespan and disrupted circadian rhythm. They showed that rapamycin increased the lifespan of the Bmal1−/− mice leading Khapre et al. [KI/KI mice, which have a nuclear mutation in the mitochondrial nucleotide salvage enzyme thymidine kinase resulting in reduced replication of mtDNA and mtDNA instability. Rapamycin dramatically increased the lifespan of the TK2KI/KI without having any detectable improvement in mitochondrial dysfunction. The authors concluded that rapamycin enhanced longevity in the TK2KI/KI mice through alternative energy reserves and/or triggering indirect signaling events. Johnson et al. [Ndufs4−/− mice, which lack a subunit in mitochondria complex I and is a mouse model of Leigh syndrome. Johnson et al. [Ndufs4−/− mice, especially at very high doses of rapamycin, which were 28-fold higher than the dose of rapamycin initially showed to increase the lifespan of mice by Harrison et al. [Leprdb mouse. They found that rapamycin doubled the lifespan of female mice but had no effect of the lifespan of male mice. Rapamycin improved both kidney and cardiac functions in the female BKS-Leprdb mice.Table s et al.  showed te et al.  studied e et al.  to propoe et al.  studied n et al.  initialln et al.  subsequen et al. . Reifsnyn et al.  studied leprdb/db mice, 13% in males and 15% in females. The reduced lifespan of the db/db mice by rapamycin was associated with an increase in suppurative inflammation, which was the primary cause of death in the db/db mice. Ferrara-Romeo et al. [Terc−/−) 16% compared with over a 50% increase in the lifespan of the G2-Terc+/+ mice. Fang et al. [Although the overwhelming majority of studies on the effect of rapamycin on longevity in mice have shown a significant increase in lifespan, there are five studies that have reported either no effect or reduced lifespan when treated with rapamycin. Two studies using transgenic mouse models of amyotrophic lateral sclerosis (G93A and H46R/H48Q) reported no increase in lifespan when given rapamycin , 27. Sato et al.  reportedg et al.  found thRapamycin would be predicted to reduce the progression of cancer because it has been shown to inhibit cell growth and proliferation. In addition, mTOR is frequently hyperactivated in cancer, and mTORC1 has often been observed to be deregulated in a wide variety of human cancers . Data geAPCMin/+ (ApcD716) mice, which are a model of human colorectal cancer. Most human colorectal cancers have somatic mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, and APCMin/+ mice develop multiple intestinal neoplasia. The APCMin/+ mice are relatively short lived, living a maximum of ~ 200 days compared with 800 to 900 days for normal laboratory mice. Three groups [APCMin/+ mice with rapamycin or everolimus reduced intestinal neoplasia (polyp number and size) in the APCMin/+ mice. In addition, these studies showed that rapamycin or everolimus dramatically increased the lifespan of the APCMin/+ mice. For example, Hasty et al. [APCMin/+ mice.The data in Table e groups –35 showep53+/− mice. Komarova et al. [p53+/− mice; however, Christy et al. [p53+/− mice treated with rapamycin. Comas et al. [p53−/− mice; however, Christy et al. [p53−/− mice.Three groups have studied the effect of rapamycin on mice with deletions in the p53 gene, a transcription factor with broad biological functions, including as a tumor suppressor in humans . Komarova et al.  reportedy et al.  did not s et al.  reportedy et al.  did not Her-2/neu. HER2 is a member of the human epidermal growth factor receptor family and amplification/overexpression of this oncogene has been shown to play a role in certain types of breast cancer. Rapamycin treatment resulted in a modest, but significant increase in the lifespan of Her-2/neu transgenic mice [Her-2/neu transgenic mice. Hernando et al. [Ptet−/− mice, a model of leiomyosarcomas. The Ptet−/− mice develop widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, and everolimus significantly reduced the growth rate of these tumors. Livi et al. [Rb1+/− mice. The retinoblastoma gene (Rb1) was the first tumor suppressor gene identified in humans and prevents excessive cell growth by inhibiting cell cycle progression. Rapamycin increased the lifespan of the Rb1+/− mice and reduced the incidence of thyroid C cell carcinomas as well as delaying the appearance and reducing the size of pituitary tumors. Hurez et al. [Rag2−/−, and IFN-γ−/− mice. Cancer immune surveillance is reduced in these two mouse models and rapamycin increased the lifespan of both Rag2−/−and IFN-γ−/− mice; however, no data were presented on the effect of rapamycin on the incidence of tumors in these mice.Two reports have described the effect of rapamycin on transgenic mice overexpressing nic mice , 41 and o et al.  reportedi et al.  studied z et al.  studied The first indication that rapamycin might be important for the heart was the discovery that coronary stents coated with rapamycin prevented restenosis and stent thrombosis compared with non-coated or other drug-eluting stents , which lThe effect of rapamycin and rapalogs on the cardiovascular system initially was not clear, especially in humans. In clinical studies with transplant patients, rapalogs induced a negative plasma cardiovascular risk profile, e.g., an increase in LDL cholesterol and triglyceride concentrations in plasma . RapamycApoE−/− or LDLR−/− mice fed a high-fat diet to induce atherosclerotic plaque formation. All four studies showed that rapamycin reduced aortic atheromas, and Jahrling et al. [LDLR−/− mice fed a high-fat diet. Because treating transplant patients with rapalogs has been shown to increase blood levels of cholesterol and triglycerides, the four groups also measured blood levels of cholesterol in their mouse models of atherosclerosis. Three found that rapamycin treatment had no effect on blood levels of cholesterol or triglycerides groups [Table g et al.  found ths groups –53. Muels groups  reporteds groups  observedA large number of studies have evaluated the effect of rapamycin on cardiomyopathy and hypertrophy induced by physical, pharmacological, or genetic engineering in mice and rats. All nine studies show that rapamycin prevents or attenuates cardiomyopathy or hypertrophy in both mice and rats. Two studies examined the effect everolimus in rats or rapamycin in mice on myocardial infraction , 57. RapThe three studies on the effect of heart function in old mice are the most relevant to this review. The studies by Simon Melov’s group at the Buck Institute  and PetePerhaps the most unanticipated aspect of rapamycin’s biological effects, besides its anti-aging actions, is its impact on the central nervous system in mice. The limited number of early studies suggested that rapamycin might have negative effects on memory because of its effect on protein synthesis . HoweverRapamycin has also been shown to affect mouse models related to Alzheimer’s disease. The apolipoprotein Eε4 allele (APOE4) is the major genetic risk factor for Alzheimer’s disease in humans; individuals with one or two copies of this allele have a fourfold to eightfold increased risk in developing Alzheimer’s disease . Using t+) neurons in the substantia nigra pars compacta [Drosophila  and a mouse model (HD-N171-N82Q) of Huntington’s disease, they showed that rapamycin attenuated the polyglutamine (polyQ) toxicity in yw;gmr-Q120 Drosophila and enhanced various tests of motor performance in HD-N171-N82Q mice. Berger et al. [Drosophila expressing polyQ proteins and showed that rapamycin was protective against tau protein in Drosophila. Sarkar et al. (2008) showed that lithium and rapamycin exert an additive protective effect against neurodegeneration in a Drosophila model of Huntington’s disease.As shown in Table compacta , 72 and compacta . Ravikumcompacta  showed tr et al.  and Kingr et al.  showed tr et al.  found siIn addition to its positive effect on neurodegeneration, rapamycin also has a neuroprotective effective effect on neurovascular disease, brain injury, and neurodevelopmental disorders Table . Of partAn interesting observation came from the study by Halloran et al.  when theBecause rapamycin was first developed as part of a cocktail to prevent rejection in transplant patients, it is generally assumed that rapamycin is an immunosuppressant. Therefore, when it was observed that rapamycin increased the longevity of mice, there were questions about the translatability of using rapamycin to delay aging in humans because of its potential negative effect on the immune system. However, it is now recognized that rapamycin is best identified as an immunomodulator rather than an immunosuppressant , 87. BecTable Streptococcus pneumonia. Old male C57BL/6 mice (24 months) were treated with rapamycin for 4 or 20 months. Both groups of mice showed improved survival to pneumococcal pneumonia and reduced lung pathology; however, the increased survival was not statistically significant for the mice given rapamycin for 20 months. On the other hand, Goldberg et al. [One of the limitations in the current studies evaluating the effect of rapamycin on infectious agents is that almost all of the studies have used young mice (under 3 months of age). Two groups studied the effect of a same dose and formulation of rapamycin (14 ppm) used by Harrison et al.  on resisg et al.  found thg et al.  who compIn 1961, Leonard Hayflick described the phenomenon of cell senescence when he showed that human fibroblasts did not grow indefinitely in culture but underwent irreversible growth arrest . It was 2O2, bleomycin), and oncogene activation. Cao et al. [The studies listed in Table o et al.  also stuIn addition to suppressing markers of senescence, such as p16 and p21 expressions and SA-β-gal-positive cells, rapamycin reduced/prevented the SASP phenotype, i.e., the expression and secretion of proinflammatory cytokines by senescent cells. Two groups independently and simultaneously reported in 2015 that rapamycin reduced SASP produced by senescent human fibroblasts. Campisi’s group at the Buck Institute reported that rapamycin suppressed the secretion of proinflammatory cytokines produced by a variety of human cells isolated from different tissues  . BecauseNrasG12V mice. NrasG12V expression induced senescence in liver, and the SASPs produced by the senescent cells trigger an immune response in these mice. Rapamycin treatment (1 mg/kg by gavage once every 3 days) reduced SASP production in the NrasG12V mice. In studying the effect of rapamycin on various aspects of cardiac function in old mice, Lesniewski et al. [INK4A expression) in the skin that was accompanied by an improvement in the clinical appearance of the skin.Of particular interest to this review are the three studies showing that rapamycin suppressed cell senescence in vivo in mice. Castilho et al.  studied i et al.  found thi et al.  studied i et al.  showed tIn the 10 years since the initial report that rapamycin increased the lifespan of mice, there has been an explosion in the number of reports studying the effect of rapamycin on various parameters related to aging in mice. These studies have focused on determining the overall impact of rapamycin on aging processes and identifying potential mechanisms responsible for rapamycin’s pro-longevity effect. As a result of the data generated, it is now clear that there is a consensus in many areas as to the impact of rapamycin on mice, and the research reports in these areas have been described in this review. The first and most important outcome of these studies has been the demonstration that rapamycin has a robust effect on the lifespan of mice. Thirty studies have been conducted since 2009 showing rapamycin increases the lifespan of various strains and genetic models of mice  and the non-human primate, the common marmoset . Salmon’s group recently reported that 9 months of rapamycin treatment had minor effects on clinical laboratory markers  in middle-aged male or female marmosets . TherefoDetermine whether rapamycin’s effect is sex dependent in transgenic mouse models of Alzheimer’s disease: Almost all of the current studies did not identify the sex of the mice used, suggesting they used both sexes. Currently, there is no study specifically comparing the effect of rapamycin on male and female mice for any transgenic AD mouse model. As described above, rapamycin has a sex effect on longevity; the lifespan of female mice is increased more than male mice. In addition, it is well documented that gender plays an important role in Alzheimer’s disease: women are at a greater risk [ter risk . TherefoDefine timing of rapamycin administration on cognition and pathology in transgenic AD mouse models: Eight of the ten studies showing that rapamycin treatment attenuated Alzheimer’s disease were conducted early in the life of the mice; mice were treated with rapamycin before a significant cognitive deficit or amyloid burden occurred. While these studies show that rapamycin can prevent the development and progression of Alzheimer’s disease in mice, there is only limited information on whether rapamycin can reverse Alzheimer’s disease. Galvan’s group [’s group  studied ’s group  studied ’s group . When th’s group  have not’s group . They st’s group  and reve’s group , 59, 113’s group , and cog’s group , 79 in mEffect of higher levels of rapamycin on Alzheimer’s disease. All of the previous studies on Alzheimer’s disease and cognition used either 14 ppm or a similar, relatively low dose of rapamycin. It is now apparent that mice not only tolerate higher doses of rapamycin but that higher doses of rapamycin result in improved lifespan [lifespan , 35, 131lifespan  to see aStudy the effect of rapamycin on other animal models: Because many interventions that work in mice do not translate to humans, it is important to determine if the positive effects of rapamycin are seen in other animal models. For example, it would be relatively straight forward to studying the effect of various levels of rapamycin at early and late stages of Alzheimer’s disease using the transgenic AD rat models [t models , 133. Ast models  have poit models . In addit models , 137.So where do we go from here? We believe one of the first areas that should be seriously considered is taking rapamycin  to the clinic as a potential treatment of Alzheimer’s disease, as has been proposed by Kaeberlein and Galvan . Current


Tachyoryctes macrocephalus, also known as giant mole rat) is a fossorial rodent endemic to the afro-alpine grasslands of the Bale Mountains in Ethiopia. The species is an important ecosystem engineer with the majority of the global population found within 1000 km2. Here, we present the first complete mitochondrial genome of the giant root-rat and the genus Tachyoryctes, recovered using shotgun sequencing and iterative mapping. A phylogenetic analysis including 15 other representatives of the family Spalacidae placed Tachyoryctes as sister genus to Rhizomys with high support. This position is in accordance with a recent study revealing the topology of the Spalacidae family. The full mitochondrial genome of the giant root-rat presents an important resource for further population genetic studies.The endangered giant root-rat ( Tachyoryctes macrocephalus, Rüppell, 1842), also known as giant mole rat and big-headed African mole rat, is a fossorial rodent and ecosystem engineer endemic to the Bale Mountains of south-east Ethiopia. The species is naturally confined to afro-alpine grasslands, where it constructs large underground burrow systems  and three nuclear genes   and DNA extracts at the GLOBE Institute, University of Copenhagen . The DNA was extracted using the Qiagen DNeasy® Blood and Tissue Kit, and sheared to approximately 400 bp using the Covaris M220 Focused-ultrasonicator. DNA fragments were built into an Illumina library following the protocol from Carøe et al. , under permits from the Ethiopian Wildlife Conservation Association. The voucher tissue sample of e et al. , and seqe et al. , and reme et al. . For thee et al.  with defe et al.  and wereNannospalax galili as outgroup. The analysis was conducted using RaxML-HPC2 on XSEDE v8.2.12  and conducted an annotation using MITOS  – with high support, in accordance with a phylogenetic analysis based on mitochondrial and nuclear genes (Our phylogenetic tree places the giant root-rat as sister clade to the genus ar genes  (Šumberaar genes . Furtherar genes . The ful


The sTibaldi et al.’s reevaluation included both immunohistochemical and morphological examinations of the rodent lesions. The premise underlying immunohistochemical analysis is that all cells in a malignant lesion are expected to be immunohistochemically identical - i.e., monoclonal – because they are all the direct descendants of a single transformed cell , 7. By cTibaldi et al confirmed that 72 of the 78 lesions originally diagnosed by RI as malignant were, in fact, monoclonal. Tibaldi et al. thus confirmed the original RI diagnoses of malignancy in 92.3% of the aspartame-exposed rodents [Roberts’ critique is based on his review of the histological slides presented by Tibaldi et al. and on the unsubstantiated and previously refuted , 9 claimp = 0.006), including both lymphomas (p = 0.032) and leukemias (p = 0.031) [Roberts also fails to acknowledge, rebut or offer any alternative explanation for the dose-response relationship between aspartame dose and cancer incidence that was clearly evident in the RI studies and was confirmed by Tibaldi et al. Increasing aspartame exposures were associated with statistically significant increases in incidence of all hematolymphatic malignancies   and takeFacile dismissals of the carcinogenicity of aspartame put forth by vested interests can no longer be sustained. Such unsubstantiated claims can impede public health interventions and can lead to unnecessary cancers, including childhood cancers and premature deaths.


Questions were asked on demographics, protocol for root canal treatment (RCT), materials employed in different stages. Opinions were also sought on satisfaction with their practice and training needs in endodontics. Data were analyzed with SPSS version 20.0 and presented as tables and charts. Significance level was set at p≤0.05.ninety dentists undergoing postgraduate training  with mean age of 34.81 ± 5.9 years participated in the study. Root canal treatment was mostly done in multiple visits in both single and multi-rooted teeth (p=0.01), only about 15% performed the procedure on multi rooted teeth. Sixty-five (72.2%) never used Rubber dam, stainless steel files were being used by 69%, step down technique of preparation by 53.9% and Sodium hypochlorite was the major irrigant (80%) used. Obturation was majorly with Cold lateral compaction technique (94%), 57.2% delayed definitive restoration for maximum of 1 week and amalgam was still the major material used for posterior teeth as reported by 62.9% of the participants. The majority (55.6%) were not satisfied with their current knowledge and practice and most were those that did not have good undergraduate training (p = 0.05).the practice of endodontics needs standardization across the nation as it is being advocated in other countries. There is need for hands on-training on endodontics to encourage adoption of new advances in technology, as well as improve the training of postgraduate dentists in endodontics. Also, emphasis should be placed on use of rubber dam in order to minimize the spread of infection and protect the patients from aspiration of small instruments involved in endodontic procedure. Endodontics is widely practiced across the globe to alleviate pulpal pain and pathologies in order to maintain the affected tooth as a functional unit of the dental arch . Many inSeveral studies -11 have This was a cross sectional study that employed self-administered questionnaire completed by resident doctors during the update course of West African College of Surgeons and residents that attended a conference of the Nigerian society for restorative dentistry (NISORD) in the same year. The update course usually draws dentists undergoing postgraduate training in institutions across the nation. To avoid duplication, the postgraduate doctors were asked to indicate if they had already completed the same questionnaire previously. The modified questionnaire  was distNinety respondents  filled and completed the questionnaire. The mean age of participants was 34.81 ± 5.9 years. A high proportion  of the participants graduated between 2001 and 2010 and the majority (86.7%) work with the government . Table 2et al. [et al. [The participants in this study were postgraduate resident doctors undergoing training in different institutions across six geopolitical zones of Nigeria, unlike the study by Udoye et al.  on endodet al. , where met al.  and Iranet al.  where 53et al.  where th [et al.  report i [et al.  written et al. [et al. [et al. [et al. [et al. [Autoclaving as claimed by 82.2% is the major means of sterilizing instruments and files. Though the use is higher in this study, it is also a major mode of sterilization in a study by Gupta et al.  where 48et al. . This stet al. . This fiet al. , Mehta e [et al.  and Küçü [et al. , that re [et al. ,9-16. Wh [et al.  and Iqba [et al.  respecti [et al.  reported [et al.  and Flem [et al. , the peret al. [et al. [et al. [Though new modifications are available to overcome the possible disadvantage (in application) of the old and conventional rubber dam kit, yet majority still do not use it. Reason for no use may include extra cost of rubber dam, lack of training, unavailability and unacceptability as observed by Gupta and Rai,  and Udoyet al. . The majet al. . Howeveret al. . This st [et al.  who obse [et al. ,17 have  [et al.  in their [et al. . The extet al. [et al. [Also, with excessive use of hand files, separation of these instruments within the canal is experienced often. As observed in this study, over 40% of the participants experienced instrument separation and this could be due to over-use. The technique of preparation of canal that involves the early coronal flaring, for example, crown-down technique has been found to produce a better shape, prevention of transportation of debris and micro-organisms to the apex, and enhanced penetration of irrigating solution. However, this study like many others -9, obseret al.  which ha [et al. . Possibiet al. [et al. [The irrigant of choice in this study was majorly sodium hypochlorite which is similar to what has been reported by several studies ,3,12-17. [et al.  and its  [et al. .et al. [Cold lateral compaction technique has been reported as the most frequently employed technique of obturation by several studies ,9,17-20 et al.  this mayet al. [Almost half (48.9%) of the participants in this study restore the access cavity a week after obturation. It is recommended by the American Association of Endodontists (AAE)  that reset al. . This iset al. ,3,12 alset al. . RelativThis study showed that some practices are in line with the recommendations for endodontic practice. However, the practice of endodontics in the country needs to be standardized across the nation as it is being advocated in some other countries, for effective management of the patients. There is also a need for continuing medical education (CME) and hands on-training on endodontics for dentists, to encourage adoption of new advances in technology, as well as improve postgraduatetraining in endodontics. Also emphasis should be placed on use of rubber dam in order to minimize the spread of infection and protect the patients from aspiration of small instruments involved in endodontic procedure.Studies have reported that most general dental practitioners have low adherence to use of international guidelines for endodontics;Though better amongst studied group compared to what is known with general dental practitioners, use of latest techniques and materials in endodontics is poor;Use of rubber dam is not commonly practiced both in the studied group and internationally.This study has shown that undergraduate training in endodontics may be insufficient as many of the respondents were not satisfied with it. Thus, need to intensify endodontic training at undergraduate level;Study observed the non-use of rubber dam for endodontics among the studied group. Therefore, there is need to lay emphasis on use of rubber dam as a standard practice of endodontic treatment;Also, the study showed the need to optimize endodontic training at postgraduate level with hands-on for better knowledge in endodontics.


Sir,I thank Shimizu et al. for their interest in our paper entitled “Efficacy of probiotics in the prevention of VAP in critically ill ICU patients: an updated systematic review and meta-analysis of randomized control trials” . We are P = 0.07; I2 = 65%) was seen between the studies. After adding this study, it can be seen that the trend favors probiotics in reducing the risk of diarrhea in ventilated patients though the effect is not statistically significant.Most previous meta-analysis such as by Su et al. and Johnstone et al. , 4have mThe use of probiotics has been well known to be associated with the reduction of C. difficile-associated diarrhea as supported by Goldenberg et al.  and Goka


The current COVID-19 pandemic threatens human life, health, and productivity. AI plays an essential role in COVID-19 case classification as we can apply machine learning models on COVID-19 case data to predict infectious cases and recovery rates using chest x-ray. Accessing patient’s private data violates patient privacy and traditional machine learning model requires accessing or transferring whole data to train the model. In recent years, there has been increasing interest in federated machine learning, as it provides an effective solution for data privacy, centralized computation, and high computation power. In this paper, we studied the efficacy of federated learning versus traditional learning by developing two machine learning models using Keras and TensorFlow federated, we used a descriptive dataset and chest x-ray (CXR) images from COVID-19 patients. During the model training stage, we tried to identify which factors affect model prediction accuracy and loss like activation function, model optimizer, learning rate, number of rounds, and data Size, we kept recording and plotting the model loss and prediction accuracy per each training round, to identify which factors affect the model performance, and we found that softmax activation function and SGD optimizer give better prediction accuracy and loss, changing the number of rounds and learning rate has slightly effect on model prediction accuracy and prediction loss but increasing the data size did not have any effect on model prediction accuracy and prediction loss. finally, we build a comparison between the proposed models’ loss, accuracy, and performance speed, the results demonstrate that the federated machine learning model has a better prediction accuracy and loss but higher performance time than the traditional machine learning model. The current COVID-19 pandemic, caused by SARS CoV2, threatens human life, health, and productivity . AI and The concept of federated learning was proposed by Google in 2016 as a new machine learning paradigm. The objective of federated learning is to build a machine learning model based on distributed datasets without sharing raw data while preserving data privacy , 5.In federated machine learning, each client  has a dataset and his local machine learning model. There is a centralized global server in a federated environment that has a centralized machine learning model , which aggregates the distributed client’s model parameters (model gradients). Each client trains the local machine learning model locally on a dataset and shares the model parameters or wights to the global model. The global model makes iteration of rounds to collect the distributed clients model updates without sharing raw data , 5 as shWhy federated machine learning should be used:Decentralized model removes the need to transfer all the data to one server to train the model, as training each node occurs locally, unlike traditional machine learning which requires moving all the data to a centralized server, to build and train the model.No data privacy violation as it applies methodologies including the differential privacy and the homographic Secure multiparty computation, unlike traditional machine learning.A third-party can be part of the training process as long as there is no data privacy violation and data is secured, unlike traditional machine learning third-party could not be an option in case of military organizations.Less computation power is needed as model training is performed on each client, and the centralized model’s primary role is to collect gradient update distributed models, unlike the traditional machine learning which one centralized server contains all the data, which requires high computational power for model training.Decentralized algorithms may provide better or the same performance as centralized algorithms .It is highly recommended to use federated machine learning rather than traditional machine learning, in such environments where data privacy, is highly required. Federated learning can be applied in many disciplines like  Federated machine learning enables us to overcome the obstacles faced by the traditional machine learning model as:Traditional machine learning occurs by moving all data source to a centralized server to train and build the model, but this may violate the rules of military organizations especially when third-party is used to create, train and maintain the model.To train the model, the third-party should prepare, clean, and restructure the data to be suitable for model training, however, this may violate data privacy when the data are handled to create the model.Traditional machine learning models also take much time to build the model with acceptable accuracy, which may cause a delay for organizations, especially recently opened ones.Traditional machine learning also requires the existence of a massive amount of historical data to train the model to give acceptable accuracy (Cold Start) .There is a need for a secure distributed machine learning methodology that trains clients’ data on their servers without violating data privacy, saves computational power, and overcomes the cold start problem, enabling clients to get immediate results.Federated learning has the potential to solve these issues, as it enables soiled data servers to train their models locally and to share their model’s gradients without violating patient privacy .The principal objective of this paper is, to build a comparison between a federated machine learning model and a non-federated machine learning model, by applying them to the same datasets and build the comparison between the model’s prediction loss, prediction accuracy, and training time.Boyi Liu et al. [%, 91.26%), second, the COVID-Net and MobileNet-v2 had the same loss value as COVID-Net and Mobile Net. Non-federated learning was conducted on the same data and it was found that the loss convergence rate caused by using federated learning decreased slightly.u et al.  proposedJunjie Pang et al. [g et al.  proposedWeishan Zhang et al. [g et al.  proposedThey defined a max waiting time for each client to participate during the server round which was defined by the platform owner. They applied four models using this architecture. GhostNet, ResNet50, and ResNet101 were used on COVID-19 datasets and they found that the proposed approach introduce better accuracy than the default setting one and can reduce communication overhead and the training time for ResNet50 and ResNet101, however, these results did not apply to GhostNet.Parnian Afshar et al. [r et al.  proposedChaoyang He et al. [%accuracy in only a few hours compared to 77.78% for FedAvg.e et al.  proposedAmir Ahmad et al. [d et al.  proposedNikos Tsiknakis et al. [s et al.  introducMwaffaq Otoom et al. [% prediction accuracy.m et al.  proposedThanh Thi Nguyen et al. [n et al.  proposedFatima M Salman et al. [% prediction accuracy.n et al.  ProposedN Narayan Das et al. [s et al.  proposedAKMB Haque et al. [e et al.  proposedHimadri Mukherjee et al. [e et al.  proposedIke FIBRIANI et al. [I et al.  proposedHarsh Panwar et al. [r et al.  proposedShashank Vaid, et al. [, et al.  proposedRodrigo M Carrillo-Larco et al. [o et al.  proposedFadoua Khmaissia et al. [a et al.  proposedAkib Mohi Ud Din Khanday et al. [y et al.  proposedR Manavalan et al. [n et al.  proposedSina F Ardabili et al. [i et al.  proposedSara Hosseinzadeh Kassan et al. [n et al.  proposedIwendi, Celestine, et al. [, et al.  proposedJaved, Abdul Rehman, et al. [, et al.  presenteBhattacharya, Sweta, et al. [, et al.  presenteManoj, Mk, et al. [, et al.  proposedReddy, G. Thippa, et al. [, et al.  proposedAnwaar Ulhaq et al. [q et al.  introducq et al. , authorsThis section addresses the applied tools and methodology for the federated and traditional one, to predict recovery based on the features of the patient. Tensor flow with Keras API was used to build federated and traditional mode, following steps were used for building models:Algorithm 1. The Federated Learning ModelInput: COVID-19 Dataset as CSV fileOutput: Model Prediction Accuracy and lossInitialization:Data Loading (data loaded using pandas package which returned data frame object with data).Drop Unique Values Column .Replace Null Values .Label Encoding .Data Repetition (data were repeated to simulate the number of clients).Data Shuffling (data shuffled to avoid getting the same results).Data Batching (data grouped into batches to enhance performance).Data Mapping (ndarray dataset flattened to 1 darray dataset).Data Prefetching (data cached in memory for better performance).Create Deep Learning Model .from_keras_model deep learning model wrapped and built a federated learning model).Create Federated Learning Model .Model Initializing and Training .Model Evaluation .Return the machine learning model accuracy and loss for each round.Algorithm 2. The Traditional Machine Learning ModelInput: COVID-19 Dataset as CSV fileOutput: Model Prediction Accuracy and lossInitialization:Data Loading (data loaded by pandas package which returned data frame object with data).Drop Unique Values Column .Replace Null Values .Label Encoding .Create Deep Learning Model .Model Evaluation .Return the machine learning model accuracy and loss for each round.As shown in Data LoadingCV2 package was used to read chest x-ray images from the dataset download directory, and was loaded it into the memory object. The images were resized to 244*244*3 as color images.Data NormalizingImage data was divided by 255 to normalize it between 1 and 0.Data ReshapingThe image object is an array of  should be flattened to be list .Creating Sample Data DictionaryAfter flattening the data dictionary instance was created for each image sample to represent the image data (features) and its label.Creating Samples and labels Tensors keras ObjectsTo build keras the dataset, the keras tensor object should be built for features and keras tensor object for labels.Create Keras Tensor Datasetfrom_tensor_slices API.Create keras dataset by using Data RepetitionData repeated to simulate the number of clients.Data ShufflingData shuffled to avoid obtaining the same results.Data BatchingData grouped into batches to enhance their performance.Data Mappingndarray dataset flattend to 1 darray dataset.Data PrefetchingData cached in memory for better performance.Create Keras Deep Learning ModelSequential deep learning model built using Keras API.Create Federated Learning Modelfrom_keras_model deep learning model.Using Keras API Create a Federated Average Processcollecting local models gradients and updates to be sent to the global model.Model Initializing and TrainingInitiated the iterative process and start training.Model EvaluationEvaluate the model performance by print evaluation metrics.As shown in Steps to be removed:Data Normalization.The data is not all the same type.Data ReshapingSteps to be addedFeatures One-Hot Encoding.Convert features categorical values to binary vectors.We modified the proposed model before model training with the Patient’s Descriptive Data.As shown in Data LoadingCV2 package was used to read chest x-ray images from the dataset download directory, it was loaded it into the memory object. The images were resized to 244*244*3 as color images.Data Normalizing.Image data was divided by 255 to normalize it between 1 and 0.Creating Sample Data Dictionary.A dictionary instance was created for each image sample to represent the image data (features) and its label.Creating Samples and labels list Objects.List object were be built for features and labels.Data Reshaping.The image object was an array of  should be flattened to be listed.Labels Encoding .To build a matrix of vectors of binary values representing categorical values of labels.Create Keras Deep Learning ModelSequential deep learning model created using Keras API.Model Initializing and Training.The iterative process initialized and start training.Model Evaluation.Model performance was evaluated by print evaluation metrics.As shown in Steps to be removed:Data NormalizationData ReshapingSteps to be added:features One-Hot Encoding.The patient’s descriptive COVID-19 datasets contained COVID-19 case information, and after training the two proposed models were used to predict the patient recovery rate. We found that:The proposed federated model had a higher prediction accuracy than the proposed traditional model As shown in The proposed federated model had lower prediction loss than the proposed traditional model As shown in The proposed federated model had high training time than the proposed traditional model As shown in After training the federated and traditional models were used to predict the outcome for a patient  based on the chest x-ray image. We found that:The proposed federated model with SGD algorithm had a higher prediction accuracy than the proposed traditional model As shown in The proposed federated model with SGD algorithm had a lower prediction loss than the proposed traditional model As shown in The proposed federated model had a high training time than the proposed traditional model As shown in After training, the federated and traditional models were used to predict the patient status  based on the chest x-ray image. We found that:The proposed federated model with SGD algorithm had a higher prediction accuracy than the proposed traditional model As shown in The proposed federated model with SGD algorithm had a lower prediction loss than the proposed traditional model as shown in The proposed federated model with SGD algorithm had a training time equal or slightly greater than the proposed traditional model as shown in Our experiments were conducted by machine was shown in Table 4In this work, two types of COVID-19 datasets were used:https://www.kaggle.com/prashant268/chest-xray-covid19-pneumonia.Patients chest x-ray radiography images (CXR) with COVID19, PNEUMONIA, and NORMAL images were obtained from https://www.kaggle.com/sudalairajkumar/novel-corona-virus-2019-dataset.Patient’s chest x-ray radiography (CXR) images datasets.www.kaggle.com, the dataset contains 5144 images categorized as follows:* 3,418 images for pneumonia cases* 1,266 images for normal cases* 460 images for COVID-19 casesDataset contains chest x-ray radiography images (CXR) with COVID19, PNEUMONIA, NORMAL images cases were obtained from Patient’s descriptive COVID-19 datasets contained COVID-19 infected cases information .* Remove unique columns.* Replace null values.* Normalize columns like age column instead of  to be .* Remove string columns.Modifications were required before feeding the machine learning model with the data like:Patients descriptive datasets with COVID-19 infected cases reported by WHO in Wuhan City, Hubei Province of China from 31 December 2019 provided by The following The model parameters modified multiple times to achieve maximum accuracy and minimum loss. These modifications included:Activation functionModel optimizerLearning rateNumber of roundsData SizeActivation functionThe sigmoid activation function was more accurate than the relu activation function.Model OptimizerChanging the SGD provided a better model accuracy and loss than ADAM, As shown in Learning Rate:it is found that changing the learning rate had a slight effect on model accuracy and model loss, when changing the learning rate from 0.02 to 0.01, the model loss changed from 34.02 to 34.04, As shown in Number of rounds:Increasing the round number affects the loss but not model accuracy, As shown in Figs Data SizeIncreasing the data size did not affect the model loss or accuracy, As shown in Figs We applied a proposed federated learning model on COVID-19 datasets, and found thatThe proposed federated learning model gives better prediction accuracy than traditional deep learning model.The proposed federated learning model gives a lower loss than traditional machine learning model.The proposed federated learning model takes a higher training time than traditional machine learning model.Activation function.The softmax activation function was more accurate than relu, sigmoid activation function when applied to the chest x-ray (CXR) images dataset and patient’s descriptive data.Model optimizerChanging the SGD provided better model accuracy and loss than ADAM when applied on patient’s descriptive data and patient’s chest x-ray (CXR) images dataset.Learning rateChanging the learning rate had a slight effect on model accuracy and model loss when applied on patient’s descriptive data and chest x-ray (CXR) images dataset.Number of roundsIncreasing the number of rounds had a good effect on reducing the loss but had no impact on model’s accuracy when applied to the patient metadata and the chest x-ray image (CXR) data set.Data SizeIncreasing data size did not affect the model loss or model accuracy when applied to patient’s descriptive data and chest x-ray (CXR) images dataset.Swarm intelligence algorithms will be used in the future to optimize the proposed federated model for global optimization and reduce the communications overhead. The hybrid model should be tested on chest x-ray radiography (CXR), and chest computed tomographyS1 Dataset(RAR)Click here for additional data file.


Global food security and sustainability in the time of pandemics (COVID-19) and a growing world population are important challenges that will require optimized crop productivity under the anticipated effects of climate change. Agricultural sustainability in the time of a growing world population will be one of the major challenges in the next 50 years. Zinc (Zn) is one of the most important essential mineral nutrients required for metabolic processes, so a shortage of Zn constrains crop yield and quality worldwide. Zinc efficiency and higher growth and yield when there is low Zn supply make it a promising sustainable solution for developing cultivars that are zinc efficient.Future crop plants need to be more Zn efficient with sustainable food yields under sub-optimal Zn conditions. Therefore, there is a substantial value in biological research aimed at understanding how plants uptake and utilize Zn.Plants” that provide an overview of current developments and trends in the times of high-throughput genomics and phenomics data analysis. Furthermore, this Special Issue presents research findings in various experimental models and areas ranging from maize to Medicago , flax, and sorghum.A total of 11 articles are included in this Special Issue of “Hacisalihoglu [alihoglu  outlinesMallikarjuna et al. [a et al.  describeAnisimov et al. [v et al.  have useCardini et al. [i et al.  have useDesta et al. [a et al.  focused Lozano-Gonzales et al. [s et al.  have useGrujcic et al. [c et al.  have useReynolds-Marzal et al. [l et al.  have usePetschinger et al. [r et al.  have useHacisalihoglu and Armstrong [rmstrong  have useOverall, the contributions to this Special Issue topic spans the full spectrum of Zn in plants and soils, cellular mechanisms, gene expressions, and biofortification. This Special Issue is an excellent summary of current progress with future outlooks that illustrates our increased knowledge on Zn and provides the foundation for further future research on the improvement of Zn nutrition in plants.Finally, we encourage the readers to visit the articles published in this Special Issue of “Unraveling the Mechanisms of Zn Efficiency in Crop Plants: From Lab to Field Applications”.


This paper aimed to review the databases on non-displaced femoral neck fractures in elderly patients. We also discussed the surgical and non-surgical treatments and selection of implants.Reviewed was the literature on non-displaced femoral neck fractures in elderly patients. Four major medical databases and a combination of the search terms of “femoral neck fractures”, “nondisplaced”, “undisplaced”, “non-displaced”, “un-displaced”, “aged”, “the elderly”, and “geriatric” were used to search the literature relevant to the topic of the review.Patients who were unable to tolerate the operation and anesthesia could be treated conservatively. Otherwise, surgical treatment was a better choice. Specific surgical strategies and implant selection were important for the patient’s functional recovery.The non-displaced femoral neck fractures are relatively stable but carry a risk of secondary displacement. Surgical treatments may be a better option because the implants provide additional stability and allow early exercise and ambulation. Hemiarthroplasty is also an alternative for old patients with higher risks of displacement and avascular necrosis of the femoral head. The femoral neck fracture is one of the most common fractures in the elderly, which seriously threatens and affects the patients’ health and quality of life , 2. CurrThe femoral neck fractures are classified into Garden type I and II (NDFNFs) and Garden type III and IV  Table . The NDFThis paper aimed to review the databases on NDFNFs in elderly patients. We also discussed their surgical and non-surgical treatments and selection of implants.We searched PubMed, ScienceDirect, Scopus, and Embase by using the terms “femoral neck fractures”, “nondisplaced”, “undisplaced”, “non-displaced”, “un-displaced”, “aged”, “the elderly”, and “geriatric”. All relevant titles and abstracts were reviewed. We read the full articles in the scope of the stated purposes, and the information supporting this review article was extracted. The flow chart depicting the strategy for selecting the relevant research is presented in Fig. Our inclusion criteria included: (1) clinical research; (2) patients with femoral neck fracture; (3) patients aged above 65 years old; (4) type I or II femoral neck fractures against the Garden classification; (5) clinical interventions including conservative treatments, internal fixation, and joint replacement. The exclusion criteria were: (1) duplicate publications; (2) patients with a failed internal fixation or revision operation after the initial joint replacement; (3) preoperative heart failure or mental disorder; (4) old or pathological fractures and rheumatoid arthritis; (5) the inconsistent outcome indicators.A total of 149 articles were included in the retrieval process, and the records after duplicate removal were 87. Furthermore, after excluding the case reports, case series, review articles, conference abstracts, expert opinions and incomplete data sets, a total of 23 full-text articles were ultimately included in the final review.et al [et al [Both Garden type I and II fractures are NDFNFs. Garden type I fractures can be treated conservatively, but misdiagnosis and osteoporosis may lead to secondary displacement . The comet al  revealedl [et al  also revl [et al –12.etc, which increase the total cost, morbidity, and mortality [Compared to the surgical treatments, conservative treatments are associated with much more mobility restrictions, bed-related complications, family care, ortality , 9, 13.Surgical treatments mainly include internal fixation and joint replacement , which are systematically reviewed and summarized in the following sections.et al [Kim et al  studied et al [et al [Many implants are used for treating NDFNFs, including cannulated screws, cancellous bone screws, dynamic hip screws, targon system, emerging dynamic locking plates, and full-thread headless compression screws. The posterior retroversion angle is closely related to the prognosis of the patients with NDFNFs. The retroversion of femoral head and frequently associated comminution of the posterolateral wall compromise blood supply of the femoral head , 16. Palet al  reviewedl [et al  also suget al [Cannulated screw is one of the ideal choices for the fixation of NDFNFs in elderly. Chen et al  treated et al , 21. Moret al .et al [et al [et al [Fixation with the cancellous bone screw is also one of safe and effective surgical approaches. Lee et al  conductel [et al  found thl [et al  also shoet al [et al [Dynamic hip screws effectively treat NDFNFs with few complications and a low re-operation rate. Compared to the cannulated screws, patients treated with dynamic hip screws had a higher Harris score one year after surgery and a lower re-operation rate , 26. Watet al  conductel [et al  studied et al [Recent studies have revealed that those systems were associated with a low incidence of postoperative complications in NDFNFs . Compareet al  used emeet al [Most patients experienced the postoperative femoral neck shortening, resulting in the varus hip and poor gait function. Chiang et al  treated et al [In NDFNFs, nonunion and late collapse of the femoral head are the two major complications. Patients aged 69 or younger have a high risk of ONFH after percutaneous screw fixation . Moreoveet al  examinedIn recent years, hemiarthroplasty is increasingly performed in elderly NDFNFs. According to the statistics of the Norwegian fractures data center, NDFNF patients treated with hemiarthroplasty rose from 2.1% in 2005 to 9.7% in 2014 .et al [et al [vs. 21.4%). Only the surgical methods had a significant impact on the occurrence of re-operation as shown by a Cox proportional hazard regression model. There were no significant differences between the two treatments in survival time and mean Harris score 5 years after surgery. However, hemiarthroplasty resulted in a significantly higher excellent-to-good rate. In addition, given nearly one-third of the elderly patients have combined dementia, following the postoperative rehabilitation instructions is difficult. Therefore, internal fixation may be a better choice in these patients [Although different types of internal fixation have been widely acknowledged in the treatment of NDFNFs, Lin et al  found thl [et al  conductepatients .et al [Regarding this, Olofsson et al  conducteet al –44. Curr et al [vs. $25,356) [ et al [Currently, the optimal treatment for NDFNFs is still controversial because few RCTs with a high level of evidence were conducted. The major considerations include postoperative function, complications, reoperation rate, and total cost , 45–47.  et al  indicate$25,356) . However$25,356) –50. Dola [ et al  conducte [ et al –56. 3D pThe NDFNFs are relatively stable but carry a risk of secondary displacement. Surgical treatments may be a better option because the implants provide additional stability and allow early exercise and ambulation. Hemiarthroplasty is an alternative treatment for elderly patients with higher risks of displacement and avascular necrosis of femoral head.


Cancers, “The Biological and Clinical Aspects of Merkel Cell Carcinoma”, walks the avid reader through the interesting and sometimes even mysterious facets of Merkel cell carcinoma (MCC), starting at its carcinogenesis to also cover innovative treatment options.The Special Issue in The groundworks for MCC and its causative agent Merkel cell polyomavirus (MCPyV) are laid in an exhaustive review by Pietropaolo et al. . They prTo date, the effective treatment options for advanced MCC are still limited. In this issue, an interesting article by Sarma et al.  tested tTurning to clinical patient care, Sahi et al. , portrayRare cancers pose a major challenge to the medical and scientific community . Due to Note added in Proof:It is often thought that the rarity of a specific cancer, such as MCC, causes patients to being “under-diagnosed” and to receive “under-treatment”, which is both unfortunately true. Published data on rare cancer are frequently based on a few patient cases or minor series with inadequate reporting , resultsAfter preparation of this editorial, two additional manuscripts were accepted. Horny et al.  revealed


Marital Stability and Quality of Couple Relationships after Acquired Brain Injury: A Two-Year Follow-Up Clinical Study’. The authors identify several demographic and clinical factors that are related to the quality of couple relationships following acquired brain injury (ABI). More specifically, they employ regression analyses to determine which factors predict (1) the functioning of couples as measured by the Dyadic Adjustment Scale  and (2)ale (DAS ). ResultThe article’s focus is highly relevant given the often drastic effects of ABI on romantic relationships ,5 and thn = 35), and the rather large number of predictors (11) in the regression analyses, the study’s analyses may have been underpowered. Using the G*Power software [a is set at 0.05 showed that a sample size of 123 would be needed to detect medium effects (2f = 0.15). Consequently, with the current approach, one might incorrectly assume that (some of the) factors included in the study are unrelated to relationship quality, while in fact they may have failed to reach statistical significance only because of the lack of power.However, given the relatively small sample size  and more research is needed, their results indicated that social cognition impairments may indeed play an important role in couple relationships following ABI. In addition, it is conceivable that social cognition impairments may function as a confounding variable in some of the relations investigated by Laratta et al. [Although it was probably not an option for Laratta et al. , given ta et al.  as they a et al.  and relia et al. .In conclusion, Laratta et al.  address