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Carpenter and colleagues analyze organ donors to find that pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of pancreatic ductal adenocarcinoma, are highly prevalent in the average healthy adult starting from a young age. Why these precursor lesions do not progress to cancer in most people is a mystery. See related article by Carpenter et al., p. 1324 (1).
Clozapine is a very effective therapeutic option for schizophrenic disorders that have been refractory to most other therapies. This extremely positive aspect clashes easily with an adverse effect of the drug that is deemed to be a very dangerous one: agranulocytosis. We asked whether the mandatory strict hematological follow-up prescribed in the black box warning of clozapine's label is proportioned to the actual incidence of agranulocytosis, considering that is the main reason that such a drug is often used only late in the treatment course. We carried out a systematic review of reports examining clozapine administration and agranulocytosis incidence. We specifically selected those where mild and moderate neutropenia was not used as a trigger to stop administration of clozapine, to better estimate the sheer incidence of agranulocytosis when clozapine was continued even with mild hematological effect, where detected. We used PubMed, MEDLINE, EMBASE, Cochrane, and ScienceDirect databases to identify clinical studies conducted between January 1975 and April 2023. We included 14 studies, mostly retrospective ones, that examined the incidence of hematological adverse effects in patients using clozapine. A total of 2354 subjects were included. The mean age of the subjects was 33.5 years. The mean duration of observation of subjects who took clozapine was 800 days, with a mean daily dose of 319.5 mg per day. Of the 2354 subjects examined, we found that 11 of them experienced agranulocytosis (0.47%). These results suggest the evidence of a lower incidence of agranulocytosis than previously estimated and are in line with more recent meta-analyses. We may therefore think that clinical practice may demand a revision of the approach that both psychiatrists and supervising organizations often take when talking about clozapine.
Artificial intelligence (AI) has grown in prominence over the decade and continues to advance frighteningly. With additional research in the computer hardware field, the accuracy and precision of AI models will increase exponentially. The interdisciplinary nature of AI expands the possibility of application in every field of study. The use of AI in human healthcare has also been on the rise, with the involvement of interactive models. Since drug development is a prominent part of the field, there are bound to be AI models capable of improving parameters and predictions for various techniques. This review explores the recent developments in the applications of AI in the scope of drug discovery. Focusing on the workflow of a standard interdisciplinary drug discovery approach, this review aims to provide information about various AI-enabled tools in the field. We begin with an in-depth overview of the different AI models and architectures frequently employed in the field. Next, we reviewed the applications of AI in drug discovery, discussing the state-of-the-art models and tools employed for topics such as data analysis, functional annotation, virtual screening, clinical trial optimization, and much more. Discussing the prospects, challenges, and limitations that the field faces, this review attempts to encompass the essence of AI-based drug discovery. We anticipate this review will aid the innovation of more brilliant AI tools for various subtopics of the drug discovery and development field.
Evidence suggests that adolescent girls are struggling in everyday life, possibly contributing to rising mental health difficulties in this group. A better understanding of their situation is required, yet accessing their daily lives is challenging. This study adopted a novel approach, combining Interpretative Phenomenological Analysis with mobile-phone video diaries to explore how adolescent girls experience and make sense of their everyday lives, with a particular focus on what matters most to them. Participants aged 16-17 recorded diaries for two-weeks and were interviewed about the areas identified. Three themes: Sacrificing now under the weight of the future, The future is coming frighteningly fast and I'm not ready to be an adult and Don't relax: struggling with relentless pressure and worry, reveal anguish caused by constantly looking towards the future, bringing a new perspective to this area and highlighting the need to help adolescent girls create space and value in their lives.
Cervical cancer (CC) is a global threat to women and our knowledge is frighteningly little about its underlying genomic contributors. Our research aimed to understand the underlying molecular and genetic mechanisms of CC by integrating bioinformatics and network-based study. Transcriptomic analyses of three microarray datasets identified 218 common differentially expressed genes (DEGs) within control samples and CC specimens. KEGG pathway analysis revealed pathways in cell cycle, drug metabolism, DNA replication and the significant GO terms were cornification, proteolysis, cell division and DNA replication. Protein-protein interaction (PPI) network analysis identified 20 hub genes and survival analyses validated CDC45, MCM2, PCNA and TOP2A as CC biomarkers. Subsequently, 10 transcriptional factors (TFs) and 10 post-transcriptional regulators were detected through TFs-DEGs and miRNAs-DEGs regulatory network assessment. Finally, the CC biomarkers were subjected to a drug-gene relationship analysis to find the best target inhibitors. Standard cheminformatics method including in silico ADMET and molecular docking study substantiated PD0325901 and Selumetinib as the most potent candidate-drug for CC treatment. Overall, this meticulous study holds promises for further in vitro and in vivo research on CC diagnosis, prognosis and therapies. Communicated by Ramaswamy H. Sarma. Transcriptomic analysis through bioinformatics revealed 218 significant differentially expressed genes (DEGs) that unfolded new molecular pathways responsible for cervical cancer (CC); The PPI network sorted major hub-genes that can be accounted as potential biomarkers with prominent roles in CC progression and helpful for its diagnosis, prognosis and therapies;TFs-DEGs and miRNAs-DEGs regulatory network assessment detected transcriptional and post-transcriptional elements;The gene-set enrichment provided gene ontological terms and pathway enrichment analysis shared biological relevance of CC development;Integrated statistics and cheminformatics approaches predicted some highly potential candidate drugs against CC;All the outcomes of the study were cross-validated through survival analyses, molecular docking and literature review.
Groundnut (Arachis hypogaea L.) is an important oil crop in the tropical and sub-tropical countries. Pod and seed coat crack-inducing factors favour Aspergillus species infections and aflatoxin B1 (AFB1) contamination of groundnut. Aflatoxin B1 (AFB1), a toxic secondary metabolite of Aspergillus species, remains a global concern due to its human and animal health, and economic impacts. Thus, the study was conducted at Babile in 2018 with the objective to identify groundnut genotypes resistant to pre-harvest fungal infections, aflatoxin contaminations and associated effects in crop physiology. Seventeen advanced groundnut breeding lines including one commercial cultivar (Werer-961), were evaluated using randomized complete block design and completely randomized design under field and with four replications for laboratory experiments, respectively. Aflatoxin B1 analysis was carried out using Enzyme-Linked Immunosorbent Assay (ELISA) kits. Appropriate statistical procedures, including regression, were employed for data analyses. Highly significant (p<0.01) variation existed among the genotypes for A. flavus and A. niger infections, and the AFB1 contamination ranged from 13.98 (G14) to 1990.86 ppb (G12). The more A. flavus infection, the more reduction in harvest yield and seedling vigour. Fortunately, 53 % of the test materials were found to be resistant to AFB1 production, and frighteningly, none of the AFB1 contaminated genotypes were within the acceptable limit of the lenient standard (10 ppb). All in all, the groundnut genotype (G4) was identified as a good source of pre-harvest resistance to A. flavus infection, AFB1 contamination and seedling vigour so that its inclusion in breeding programs is worthwhile utmost, specifically, in the test environment as pathogen-crop-environment interaction is natural. Since the experiment was employed at one location and for only one year, it is suggested to repeat the experiment across multiple locations and over seasons for reliable recommendation.
Drug-resistant microorganism are a growing global danger. Strains of S. aureus have developed resistance to many commonly used antimicrobials due to indiscriminate use of antimicrobials, and treatment becoming a challenge. Studies assessing pattern and determinants of S. aureus resistance in ear infection in Ethiopia are very scarce. This study presents overview of pattern and determinants S. aureus resistance from samples of ear discharge in Ethiopia. A prospective cross-sectional study was conducted on patients who visit ENT clinic of University of Hawassa comprehensive specialized hospital from February 1, 2016 to November 1, 2016. 117 specimens were collected with sterile applicator cotton swab from 117 patients with ear discharge visiting the clinic. Data was fed and then edited, cleared, entered and analyzed using SPSS version 20. The prevalence of S.aureus infection was 28.2%. S. aureus isolates revealed up to 97.0% level of resistance pattern to the antimicrobials tested. In the determination of the susceptibility of S. aureus on nine selected antibiotics by disk diffusion technique, 97.0% of the isolates were resistant to cloxacilin and 74.2% showed resistance to vancomycin. The overall rate of MDR was 100%, all of the isolates were found to be resistant to more than two tested antimicrobials. S. aureus has gotten frighteningly resistant to many of common antimicrobials. Resistance rate to vancomyin is terrifyingly high. It urges us to take measures to delay resistance. Emergence of resistance highlights the value of prudent prescribing of antimicrobials and avoiding their irrational use. Further researches focusing on identifying dynamics promoting resistance, identifying high risk strains and molecular basis of resistance are required.
Only a high-energy force can cause thoracic spinal fracture-dislocation injuries, and such injuries should always be suspected in patients with polytrauma. The injury is usually accompanied by neurological symptoms. There are only a few cases of severe thoracic spinal fracture-dislocation without neurological symptoms in the literature, and until now, no case of severe thoracic spinal fracture-dislocation without neurological symptoms and without costal fractures has been reported. A 30-year-old Han Chinese man had T6 to T7 vertebral fracture and anterolateral dislocation without neurological symptoms and costal fractures. The three-dimensional reconstruction by computed tomography and magnetic resonance imaging indicated the injuries in detail. A patient with thoracic spinal fracture-dislocation without neurological symptoms inclines to further dislocation of the spine and secondary neurological injury; therefore, laminectomy, reduction and internal fixations with rods and screws were done. The outcome was good. Severe spinal fracture-dislocation without neurological symptoms should be evaluated in detail, especially with three-dimensional reconstruction by computed tomography. Although treatment is individualized, reduction and internal fixation are advised for the patient if the condition is suitable for operation. Severe thoracic spinal fracture-dislocation without neurological symptoms and costal fractures is frighteningly rare; an operation should be done if the patient's condition permits.
Ultraviolet (UV) radiation has affected life at least since the first life forms moved out of the seas and crawled onto the land. Therefore, one might assume that evolution has adapted to natural UV radiation. However, evolution is mostly concerned with the propagation of the genetic code, not with a long, happy, and fulfilling life. Because rickets is bad for a woman giving birth, the beneficial effects of UV-radiation outweigh the adverse effects like aged skin and skin tumors of various grades of malignancy that usually only afflict us at older age. Anthropogenic damage to the stratospheric ozone layer and frighteningly high rates of melanoma skin cancer in the light-skinned descendants of British settlers in Australia piqued interest in the health impacts of UV radiation. A changing cultural perception of the beauty of tanned versus light skin and commercial interests in selling UV-emitting devices such as tanning booths caught public health experts off-guard. Counseling and health communication are extremely difficult when dealing with a "natural" risk factor, especially when this risk factor cannot (and should not) be completely avoided. How much is too much for whom or for which skin type? How even measure "much"? Is it the (cumulative) dose or the dose rate that matters most? Or should we even construct a more complex metric such as the cumulative dose above a certain dose rate threshold? We find there are still many open questions, and we are glad that this special issue offered us the opportunity to present many interesting aspects of this important topic.
Between 1999 and 2005, a total of 41 patients were hospitalized at the Burn Centre of Brno University Hospital with high voltage electrical injuries, representing 6.06% of the total number of patients treated at the Burn Intensive Care Unit (ICU) for extensive burn trauma. The average age of patients with serious electrotraumas was 27.29 years. The youngest patient was 9 years old, the oldest 64 years. Lethality amounted to 17.07% of the total number of patients. The article clearly shows the sinister dimension (a frighteningly high number of cases) of high voltage electrical injuries suffered outside work context in the vicinity of railway tracks and affecting in particular the youngest age groups--children.
In this age of modern medicine, one would like to believe that we have come far, but it is not so with pediatric trauma. Statistics remain frighteningly high with trauma as the leading cause of death in children. It affects 1 in every 3-4 children. Up to 22 million children suffer injuries every year. In 30 years, the statistic of 50% of all childhood deaths resulting from injuries has remained unchanged, but the number of injured children continues to climb. The cost to society is in the billions. Nurses can decrease morbidity and mortality in children by understanding common patterns of injury and educating parents and children about injury prevention.
This review describes eight 'great ideas' regarding bench-to-bedside considerations in systemic lupus erythematosus (SLE) presented at the second international LUPUS meeting in Quebec, September 2014. The topics included: correcting the impaired clearance of apoptotic fragments; optimisation of clinical trial design: the PERFECT (Pre Evaluation Reducing Frighteningly Elevated Coverable Targets) study; lipidomics and metabolomics in SLE; importance of the inflammasome; identification and treatment of asymptomatic autoimmunity: prevention of SLE; combining low doses of hydroxychloroquine and quinacrine for long-term maintenance therapy of SLE; reducing emergency room visits and the critical relevance of the autoantigen.
Pediatricians form part of children's and young people's most important extra-familial relations. They are thus especially well placed: first, to discover abuse of any kind, and second to put in motion the first years of measures of assistance for the children and their families. The first years of life are decisive for effective prevention of abuse and neglect, and for the development of a healthy personality. In this part of life, pediatricians are virtually the only "social outposts". Nevertheless, in Swiss pediatrics the concept of child protection is still in the initial stages. While we should warmly welcome the fact this problem was at last the main theme of an annual meeting, it must be remembered that this was only the first time. For a long time now no one has doubted that in our, thus far socially privileged country, a frighteningly large number of children and adolescents are victims of abuse. Since the publication of the report "Mauvais traitements des enfants en Suisse" (1992) a representative questionnaire to parents has shown that in this country and now, as before, over a third of parents use corporal punishment on their children. It has been calculated that e.g. 21,800 babies aged between 0 and 2.5 years are beaten, 4800 of them even with implements. There are no data on psychological and sexual maltreatment. Despite this shocking incidence of abuse, only a total of 72 cases (6% of all recorded cases) were reported over one year by pediatric practitioners in the "1989 prospective study". We cannot accept that this reflects a lack of social concern. Many other shortcomings appear to be involved: lack of briefing on the problems of child abuse during medical training, post-graduate and continuing studies, inadequate arrangements for interdisciplinary work, discouragement and early delegation to pseudo-experts, distrust of the efficacy of available aids (but sometimes overestimation of one's own possibilities) and last but not least, a still highly idealized image of the family which prompts one to reject the possibility of abuse. The Swiss Pediatric Society is urgently called upon to focus closer attention on this subject, and in so doing to take advantage of the increasingly widespread concept that child abuse must be regarded as resulting from a disturbance of the child's social network. Here the pediatrician can find an effective, decisive and also--above all--preventive role.
Hypertension is regarded as a major contributor to vascular disease. Vascular disease is a fairly common denominator in a large percentage of cases of dementia. Despite this strong connecting link, dementia is often not considered as a mainstream problem consequent to hypertension, though there is an alarming increase in the number of cases of dementia. While established dementia has very few treatment options, prevention of development and slowing of progression of dementia by proper treatment of hypertension could be an important strategy, especially so, in a financially challenged Indian subcontinent with inhomogeneous health coverage. None of us wants to be reminded that dementia is random, relentless, and frighteningly common-Laurie Graham.
Paraneoplastic pemphigus has been established as a newly recognized but distinctive syndrome. The syndrome has distinctive clinical, histologic, and immunopathologic features that are consistent between affected individuals. It is intriguing that the autoimmune disease is associated with a very small number of unusual lymphoreticular malignancies. Its very restricted association is encouraging in that it implies there may be a common and identifiable mechanism by which these tumors induce the autoimmunity. Future important goals include the following. First, the genes that encode the as yet uncharacterized protein antigens must be identified and their exact nature determined. It is possible that one of these antigens may represent a biologically important epithelial adhesion molecule. Second, the mechanism or mechanisms by which the tumor cells drive the autoimmune disease must be determined. This may have broader implications for other paraneoplastic diseases such as tumor-associated autoimmune cytopenias or myasthenia. Finally, defining the basic mechanisms of disease induction may lead to improved treatment for the disease. At present it remains a devestating disease with a frighteningly high mortality. Fortunately, recent early diagnosis and intervention with combined prednisone-cyclosporine therapy have provided at least some hope of controlling the disease.
The 'black hole' is a signifier that pervades contemporary experience, conveying the 'gaps' and 'voids' in Western culture and psyche. Depth psychology stemmed from the growing uncanniness of city and psychic spaces during the 19(th) century. There was an emerging fascination with the 'dark Thing'--the 'It' of many names. Like a pandemic, depictions of the 'black hole' experience have continually emerged in the tragic events and cultural malaise of the twentieth and twenty-first centuries. Art, philosophy, science, psychoanalysis, literature, and cultural studies have variously articulated this frighteningly potent, yet endlessly elusive signifier. A many-sided, dialogical process best provides acquaintance with such a complex phenomenon. Multiple examples and perspectives, as well a detailed case study, will delineate some of its dimensions. They will show that such 'black hole' encounters are not merely negative, but are often the enigmatic source of new awareness and creation.
Violence against women is a universal phenomenon that persists in all communities and in all countries of the world and the perpetrator of that violence is often well-known to the victim. Domestic violence in particular continues to be frighteningly common and well-accepted as "normal" within too many societies. (1) The primary aim of this study is to find out the extent of different type of domestic violence and to identify various risk factors for domestic violence against married women. (2) The secondary aim is to identify the various protective factors of domestic violence against married women. The present study was a population based cross-sectional study carried out in the urban area of Gwalior city for a period of one year. Stratified random sampling technique was used for the selection of the samples. The study participants were interviewed using a pretested semi-structured open-ended questionnaire. Proportion, Pearson's, chi-square test and odds ratio were calculated for the analysis of the study. Of the 144 study participants, 68 participants reported some form of domestic violence, which was either physical, sexual or emotional. The most common type of violence reported was physical violence. The most important risk factor for domestic violence was alcoholism followed by literacy status. Majority of the abused women were dependent on their husbands for money, material assets and expenditure. The study hereby recommends that to prevent domestic violence government has to take stringent action for making women more self-reliant especially by making the women more literate and more financially independent.
A rapidly fatal viral infectious disease appeared in England in 1485, persisted for the summer months and disappeared as winter approached. This pattern of infection re-appeared in 1508, 1517, 1528, and finally 1551. The epidemic never returned. It had no respect for wealth or rank, and predominantly attacked males between the ages of 15 and 45 years. The incubation period was frighteningly short and the outcome normally fatal. The symptoms of acute respiratory disease and copious sweating were characteristic, providing the name 'the English sweating disease'. It was never in the big league of killer epidemics, such as plague and influenza, but its pockets of instant lethality in communities gave it a special ranking of horror. The infective cause of this disease remained a total mystery until it was compared with Hantavirus pulmonary syndrome (HPS) in 1994. The strength of this theory is examined in this paper, and it is concluded that, although there is a close resemblance, HPS does not match the English sweating disease completely and positive identification of a possible rodent carrier for the latter was not established.
Posttraumatic stress disorder (PTSD) is an uncomfortable response that can follow exposure to 1 or more dangerous or frighteningly traumatic circumstances. Symptoms often include intrusive thoughts, insomnia, nightmares, flashbacks, avoidance behaviors, and hypervigilance or related emotionally troubling experiences. When overtly present, PTSD induces considerable emotional, social, occupational, and interpersonal dysfunctions. Psychotherapy is a commonly recommended initial intervention. There are a wide variety of techniques available. Psychotherapy can also be utilized as a preventative measure when intervention is available in the immediate aftermath of exposure to a potentially precipitating event. Most combat veterans with PTSD at Veterans Administration medical centers in the United States are prescribed pharmacotherapy. Different antidepressant, antipsychotic, adrenergic, and anticonvulsant medications are most commonly utilized. Optimal intervention for patients experiencing PTSD often includes prolonged follow-up that applies both talk and drug therapies in a supportive environment. This narrative review describes psychotherapeutic and pharmacologic approaches to treat PTSD.