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Background Coronavirus disease of 2019 (COVID-19) is well known as a fatal disease, first discovered at Wuhan in China, ranging from mild to death, such as shortness of breath and fever. Early diagnosis of COVID-19 is a crucial point in preventing global prevalence. Objective We aimed to evaluate the diagnostic competency and efficiency with the Allplex™ 2019-nCoV Assay kit and the Dr. PCR 20 K COVID-19 Detection kit, designed based on the qRT-PCR and dPCR technologies, respectively. Methods A total of 30 negative and 20 COVID-19 positive specimens were assigned to the diagnostic test by using different COVID-19 diagnosis kits. Diagnostic accuracy was measured by statistical testing with sensitivity, specificity, and co-efficiency calculations. Results Comparing both diagnostic kits, we confirmed that the diagnostic results of 30 negative and 20 positive cases were the same pre-diagnostic results. The diagnostic statistics test results were perfectly matched with value (1). Cohen’s Kappa coefficient was demonstrated that the given kits in two different ways were “almost perfect” with value (1). In evaluating the detection capability, the dilutional linearity experiments substantiate that the Dr. PCR 20 K COVID-19 Detection kit could detect SARS-CoV-2 viral load at a concentration ten times lower than that of the Allplex™ 2019-nCoV Assay kit. Conclusions In this study, we propose that the dPCR diagnosis using LOAA dPCR could be a powerful method for COVID-19 point-of-care tests requiring immediate diagnosis in a limited time and space through the advantages of relatively low sample concentration and small equipment size compared to conventional qRT-PCR. Supplementary Information The online version contains supplementary material available at 10.1007/s13258-021-01162-4.

A 75-year-old man visited our hospital for the examination of a tumor in the pancreas. Computed tomography showed an 85×85-mm low-density tumor in the pancreas. The tumor was pathologically diagnosed as poorly differentiated carcinoma by endoscopic ultrasound-guided fine-needle aspiration. Although we started chemotherapy, the patient died 84 days after the diagnosis. An autopsy demonstrated a ruptured anaplastic carcinoma with mucoepidermoid carcinoma of the pancreas. Anaplastic carcinoma with mucoepidermoid carcinoma is a very rare histologic subtype of pancreatic carcinoma, so pathological findings are important for predicting the patient's prognosis. Physicians should be aware of this rare but fatal disease.

Juliane Schürmann,1 Frank Noack,2,3 Steffi Bethge,4 Viktoria Heinze,4 Axel Schlitt4,5 1Department of Cardiology and Pulmonology AMEOS Clinic Bernburg, Bernburg, Germany; 2Department of Emergency Medicine, University Clinic Halle-Saale, Halle, Germany; 3Department of Medicine I, University Clinic Halle-Saale, Halle, Germany; 4Paracelsus-Harz-Clinic Bad Suderode, Quedlinburg, Germany; 5Medical Faculty, Martin-Luther-University Halle-Wittenberg, Halle, GermanyCorrespondence: Juliane SchürmannDepartment of Cardiology and Pulmonology AMEOS Clinic, Bernburg, 06406, GermanyTel +49 3471 341504Fax +49 3471 342053Email jsch.med@bernburg.ameos.deBackground: Heart failure is the third most fatal disease in Germany and generates considerable treatment costs. The multimodal program of inpatient rehabilitation can improve the symptoms and prognosis of these patients. At the present time, however, only few data are available on the effectiveness of rehabilitation for heart failure patients.Methods: After receiving study approval from the ethics committee of the Saxony–Anhalt Medical Association, 200 patients with a primary or secondary diagnosis of heart failure were prospectively included in the study at Paracelsus-Harz-Clinic Bad Suderode, Quedlinburg, Germany. Baseline parameters such as age, gender, and BMI were documented. Outcome variables included NYHA classifications, quality of life, and mortality. For follow-up, the patients were contacted again by mail or phone after three and 12 months and, data on symptoms and serious events were recorded.Results: The proportion of patients with a highly reduced ejection fraction (HFrEF) was 13.5%, with a midrange reduced ejection fraction (HFmrEF) 33%, and with preserved ejection fraction (HFpEF) 53.5%. The mean age was 64 ± 11.9 years, the proportion of women 24.1%. The effects of rehabilitation were documented by low overall mortality (no patient died during the stay, only 4% of the patients died in the 12-month follow-up) and an improvement in NYHA classification during and after the inpatient rehabilitation.Conclusion: This monocentric study showed effects both for symptoms (improvement in NYHA classifications) and prognosis (overall mortality) after rehabilitation. These data reflect the effectiveness of multimodal rehabilitation and underscore the need for rehabilitation in patients diagnosed with heart failure after an acute event and hospital stay or who present with chronic deterioration.Keywords: heart failure, cardiac rehabilitation, inpatient rehabilitation

Background The management of brainstem glioma remains controversial, with increasing evidence supporting surgical resection as the primary treatment for a select subgroup of tumors. However, there remains no consensus on the specific benefits and risks, the selection of surgical candidates, and prognostic factors that may further refine surgical indications. Methods A retrospective single-surgeon chart review was performed for all patients who underwent surgical treatment for radiographically suspected brainstem glioma between 2000 and 2017. Preoperative and postoperative radiographic evaluations on magnetic resonance imaging were conducted. Survival outcomes were collected, and machine-learning techniques were used for multivariate analysis. Results Seventy-seven patients with surgical treatment of brainstem glioma were identified, with a median age of 9 years (range, 0–58 years). The cohort included 64% low-grade (I and II) and 36% high-grade (III and IV) tumors. For all patients, the 1-year and 5-year overall survival were 76.4% and 62.3%, respectively. Transient neurologic deficit was present in 34% of cases, and permanent deficit in a further 29%. Conclusions The radical surgical resection of brainstem gliomas can be performed with acceptable risk in well-selected cases and likely confers survival advantage for what is otherwise a rapidly and universally fatal disease. Various radiographic features are useful during patient selection and may guide treatment selection.

Objectives The aim of this study was to evaluate the diagnostic capacity of integrated pulmonary index (IPI) in predicting the pulmonary embolism (PE) in patients admitted to emergency departments (ED) with dyspnea. Background The acute dyspnea is one of the most common chief complaints in EDs. PE is a potentially fatal disease and the delay in specific therapy increases the worst outcomes. Methods This study is a prospective methodological study, in which we evaluated the diagnostic performance of the IPI in predicting PE in patients admitted to ED with dyspnea. ROC analysis was used for estimating the accuracy of IPI and OCRS. Results Of the 144 patients included in the study, there were 20 (13.9 %) PE patients. In the ROC analysis, the best cut-off point for IPI was ≤ 2. For this cut-off point, the sensitivity and specificity of IPI were 100.0 % and 96.0 %, respectively. Besides, the accuracy of IPI was 96.5 % with a +LR of 24.8 and a -LR of 0.0. Conclusion IPI was a potential candidate for evaluating the respiratory status, and a limiting tool to prevent unnecessary diagnostic tests and save time in determining the treatment course in dyspneic patients at ED (Tab. 5, Fig. 3, Ref. 34).

New data have emerged that can help guide decision making on the increasingly complex medical and surgical treatment options for women with ovarian cancer., The medical and surgical treatment strategies for women with epithelial ovarian cancer continue to evolve. In the past several years, there has been significant progress backed by landmark clinical trials. Although primary epithelial ovarian cancer is still treated with a combination of surgery and systemic therapy, more complex surgical procedures and novel therapeutics have emerged as standard of care. Cytotoxic chemotherapy and maximal surgical effort remain mainstays, but targeted therapies are becoming more widespread and new data have called into question the role of surgery for women with recurrent disease. Poly ADP-ribose polymerase inhibitors have improved progression-free survival outcomes in both the frontline and recurrent settings, and their use has become increasingly widespread. The recent creation of treatment categories based on genetic changes reinforces the recommendation that all women with epithelial ovarian cancer have germline genetic testing, and new biomarker-driven drug approvals indicate that women may benefit from somatic molecular testing as well. To continue to identify novel strategies, however, enrollment on clinical trials remains of the utmost importance. With the evolving data on surgical approaches, targeted therapies such as antiangiogenics and poly ADP-ribose polymerase inhibitors, and the new therapeutic agents and combinations in development, we hope that advanced epithelial ovarian cancer will eventually transition from an almost universally fatal disease to one that can increasingly be cured.

Aim To assess very long-term outcomes of children with severe aplastic anaemia (SAA) and impact of histopathology and of different treatments over time. Methods We conducted a retrospective study of 57 consecutive patients with SAA during 1973-2019. According to period, treatment consisted of androgens, immunosuppressive treatment (IST) and haematopoietic cell transplantation (HCT) in 14, 31 and 13 patients, respectively. Histopathology immune profiles were studied on bone marrow (BM). Results Response rate (RR) to androgens was 35%, with long-term survivorship in 4 of 5 responders. RR and 10-year overall survival (OS) after IST was 65% and 80%, respectively. RR was higher in girls (92% vs 43% in boys, P = .02). Mean baseline BM values of CD34 + and of B-lymphocytes in responders vs non-responders were 1.3% vs 0 (P = .08) and 14.1% vs 9.7% (P = .07), respectively. After IST, BM cellularity gradually increased and cytotoxic T-lymphocytes decreased (time variation P = .003 and 0.07, respectively). Outcome did not differ between patients with IST or frontline HCT. Ten-year OS improved over time, increasing from 35.3% to 77.1% and 77% during 1973-1985, 1986-2003 and 2004-2019, respectively. Conclusion Histopathology may refine response prediction to IST. The course of SAA in children, a previously fatal disease, was altered in recent times.

Immune checkpoint inhibitor (ICI) therapies have revolutionized the management of patients with NSCLC and have led to unprecedented improvements in response rates and survival in a subset of patients with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to considerable immune-related adverse events. Therefore, patient selection must be optimized through the use of relevant biomarkers. Programmed death-ligand 1 protein expression by immunohistochemistry is widely used today for the selection of programmed cell death protein 1 inhibitor therapy in patients with NSCLC; however, this approach lacks robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next-generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to ICIs. In theory, a higher TMB increases the probability of tumor neoantigen production and therefore, the likelihood of immune recognition and tumor cell killing. Although TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses, employing both tumor and blood-based sequencing tools, have evaluated the performance of TMB as a predictive biomarker, and in many cases reveal a correlation between high TMB and ICI response rates and progression-free survival. Many challenges remain before the implementation of TMB as a biomarker in clinical practice. These include the following: (1) identification of therapies whose response is best informed by TMB status; (2) robust definition of a predictive TMB cut point; (3) acceptable sequencing panel size and design; and (4) the need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to ICI therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges in the use of TMB in routine practice.

Stroke has become the most disabling and the second most fatal disease in the world. It has been a top priority to reveal the pathophysiology of stroke at cellular and molecular levels. A large number of long non-coding RNAs (lncRNAs) are identified to be abnormally expressed after stroke. Here, we summarize 35 lncRNAs associated with stroke, and clarify their functions on the prognosis through signal transduction and predictive values as biomarkers. Changes in the expression of these lncRNAs mediate a wide range of pathological processes in stroke, including apoptosis, inflammation, angiogenesis, and autophagy. Based on the exploration of the functions and mechanisms of lncRNAs in stroke, more timely, accurate predictions and more effective, safer treatments for stroke could be developed.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal disease if not diagnosed and treated promptly. HLH can be due to genetic factors or infections, malignancies and collagen-associated vascular diseases. Malignancy-associated HLH is not only more common in the setting of T/NK-cell lymphomas, but may also rarely be seen in the setting of B-cell lymphoma. Here, we describe a unique case of a patient who initially was diagnosed with HLH secondary to Epstein Barr virus (EBV) infection and subsequently developed EBV-positive diffuse large B-cell lymphoma affecting the brain. This case highlights the spectrum of findings associated with EBV infections and the challenges in diagnosing underlying diseases associated with HLH.

Cerebral amebic encephalitis due to Balamuthia mandrillaris is a rare yet typically fatal disease. As such, identification of the clinical characteristics, appropriate diagnostic workup and commencement of treatment is frequently delayed. Here, we present a case of a 4-year-old male with a B. mandrillaris cerebral abscess successfully treated with expedited neurosurgical resection and broad-spectrum antimicrobial therapy.

INTRODUCTION Progressive multifocal leukoencephalopathy (PML) is a rare infection of the central nervous system due to the reactivation of the John Cunningham polyomavirus. It is commonly a progressive fatal disease with worldwide distribution. CASE REPORT We describe a rare case of PML, which was misdiagnosed as neuropsychiatric systemic lupus erythematosus (SLE) with a catastrophic outcome due to delay in diagnosis with superadded cyclophosphamide therapy. CONCLUSION There are several lessons taught from our case. Firstly, in patients with autoimmune disorders who are strongly immunosuppressed, the new onset of cognitive impairment and seizures should alert the treating physician to look carefully for PML. Secondly, in cases of SLE where the diagnosis of the cause of cognitive impairment and seizures is not clear, we suggest that immunosuppression should not be intensified until PML has clearly been ruled out. Lastly, multidisciplinary care in patients with suspected neuropsychiatric SLE including a neurologist, an infectious diseases consultant, a neuroradiologist, and a rheumatologist is needed.

Objectives Feline infectious peritonitis (FIP), caused by genetic mutants of feline enteric coronavirus known as FIPV, is a highly fatal disease of cats with no currently available vaccine or US Food and Drug Administration-approved cure. Dissemination of FIPV in affected cats results in a range of clinical signs, including cavitary effusions, anorexia, fever and lesions of pyogranulomatous vasculitis and perivasculitis, with or without central nervous system or ocular involvement. The objectives of this study were to screen an array of antiviral compounds for anti-FIPV (serotype II) activity, determine cytotoxicity safety profiles of identified compounds with anti-FIPV activity and strategically combine identified monotherapies to assess compound synergy against FIPV in vitro. Based upon clinically successful combination treatment strategies for human patients with HIV and hepatitis C virus infections, we hypothesized that a combined anticoronaviral therapy approach featuring concurrent multiple mechanisms of drug action would result in an additive or synergistic antiviral effect. Methods This study screened 90 putative antiviral compounds for efficacy and cytotoxicity using a multimodal in vitro strategy, including plaque bioassays, real-time RT-PCR viral inhibition and cytotoxicity assays. Results Through this process, we identified 26 compounds with effective antiviral activity against FIPV, representing a variety of drug classes and mechanisms of antiviral action. The most effective compounds include GC376, GS-441524, EIDD2801 and EIDD1931. We documented antiviral efficacy for combinations of antiviral agents, with a few examined drug combinations demonstrating evidence of limited synergistic antiviral activity. Conclusions and relevance Although evidence of compound synergy was identified for several combinations of antiviral agents, monotherapies were ultimately determined to be the most effective in the inhibition of viral transcription.

Background The 100th anniversary of the discovery of insulin in Toronto in 1921 is an important moment in medical and scientific history. The demonstration that an extract of dog pancreas reproducibly lowered blood glucose, initially in diabetic dogs and then in humans with type 1 diabetes, was a medical breakthrough that changed the course of what was until then a largely fatal disease. The discovery of the “activity”, soon named “insulin”, was widely celebrated, garnering a Nobel Prize for Banting and McLeod in 1923. Over the ensuing 100 years, research on insulin has advanced on many fronts, producing insights that have transformed our understanding of diabetes and our approach to its treatment. Scope of Review This paper will review research on insulin that had another consequence of far broader scientific significance, by serving as a pacesetter and catalyst to bioscience research across many fields. Some of this was directly insulin-related and was also recognized by the Nobel Prize. Equally important, however, was research stimulated by the discovery of insulin that has profoundly influenced biomedical research, sometimes also recognized by the Nobel Prize and sometimes without this recognition. Major Conclusions By reviewing some of the most notable examples of both insulin-related and insulin-stimulated research, it becomes apparent that insulin had an enormous and frequently under-appreciated impact on the course of modern bioscience.

We report 3 cases of Puumala virus infection in a family in Switzerland in January 2019. Clinical manifestations of the infection ranged from mild influenza-like illness to fatal disease. This cluster illustrates the wide range of clinical manifestations of Old World hantavirus infections and the challenge of diagnosing travel-related hemorrhagic fevers.

Implementation of combination antiretroviral therapy (cART) has transformed HIV from a fatal disease to a chronic manageable illness. Despite this advance in treatment, a new lingering challenge has emerged in the battle against HIV, namely managing the associated comorbidities.1 Specifically, individuals with HIV have an increased risk of developing various systemic disorders, such as cancer and neurocognitive impairment.2 This risk increases as a function of life span, therefore, infected children although spared complications associated with opportunistic infections due to the efficacy of cART, are at significantly greater risk of developing chronic neurocognitive complications.2 Furthermore, children merely exposed to HIV in utero have also been shown to exhibit structural CNS abnormalities and multiple delays in neurodevelopmental milestones.3,4

Systemic capillary leak syndrome (SCLS) is a rare, potentially fatal disease characterized by the leakage of plasma and proteins through the vascular endothelium, leading to hypotension, hypoprotei...

Orthopedic surgeons are well aware of tumor contamination at the site of initial biopsy in osteosarcoma. However, tumor contamination in patients with osteosarcoma associated with thoracic instrumentation is not well described. The authors summarize 2 reported cases in addition to the 2 cases at their institution of this phenomenon. Knowledge of tumor contamination and preventative measures against tumor contamination is sparse in the literature, especially pertaining to patients with osteosarcoma undergoing thoracic instrumentation. In this report, the authors hope to increase awareness of these cases and suggest preventative measures to mitigate against tumor contamination in patients with osteosarcoma. The authors report that the median time between thoracic instrumentation and the visible detection of tumor migration to local sites was 5 months. They conclude that tumor contamination associated with thoracic instrumentation is characterized by patients with multiple sites of relapse and aggressive, fatal disease.

Pediatric diffuse intrinsic pontine glioma (DIPG) represents approximately 20% of all pediatric CNS tumors. However, disease outcomes are dismal with a median survival of less than 1 year and a 2-year overall survival rate of less than 10%. Despite extensive efforts to improve survival outcomes, progress towards clinical improvement has been largely stagnant throughout the last 4 decades. Focal radiotherapy remains the standard of care with no promising single-agent alternatives and no evidence for improvement with the addition of a long list of systemic therapies. A better understanding of the biology of DIPG, though not easy due to obstacles in obtaining pathological material to study, is promising for the development of specific individualized treatment for this fatal disease. Recent studies have found epigenetic mutations to be successful predictors and prognostic factors for developing future management policies. The aim of this review is to give a global overview about the epidemiology, diagnosis, and treatment of DIPG. We further examine the controversial biopsy and autopsy issue that is unique to DIPG and assess the subsequent impact this issue has on the research efforts and clinical management of DIPG.

Introduction: While death due to Zika virus (ZIKV) infection has been described, reports of fatal cases have been infrequent and no systematic reviews on the subject have been published. Methods: A systematic review of the literature in four databases was performed to assess fatal outcomes of postnatal ZIKV infection and the available evidence that links ZIKV infection to death. Results: Three hundred and eleven articles were retrieved; 20 of them were epidemiological reports from surveillance agencies and ministries of health. After screening by abstract and title, 59 articles were selected for full-text assessment. Of these, 35 were excluded (with reasons) and 24 were finally included for qualitative analysis. A total of 51 reported deaths associated with ZIKV infection in nine countries were identified. The majority of cases (56.9%) were not related to Guillain–Barré syndrome. Cases from three countries accounted for 67.6% of the deaths. ZIKV infection was laboratory-confirmed in the majority of cases (64.7%). Discussion: ZIKV was not considered to be a dangerous, and much less a lethal pathogen, until very recently. However, an increasing number of fatalities have been published in the literature since the first death was reported in 2016. Additional research is needed to elucidate factors that may mediate the pathogenesis of severe, atypical, and fatal disease. Keywords: Zika, Fatal, Complications, Severe, Epidemiology, Americas

Rabies is a fatal disease that mandates proper prophylaxis after a rabies virus exposure to prevent death. This study evaluated adherence to Centers of Disease Control and Prevention (CDC) recommendations for rabies immune globulin (IG) patient selection, dosing, timing of administration, and anatomical site of administration for rabies postexposure prophylaxis. This retrospective, cross-sectional study included patients who received at least one dose of rabies IG or rabies vaccine at a multi-hospital health system from January 2015 through June 2018. This study included 246 patients, and all of them received at least one dose of rabies vaccine. Two patients had a history of rabies vaccination, did not have an indication for rabies IG, and appropriately did not receive additional rabies IG. Rabies IG was administered to 91% (223 of 244) of patients with an indication. Of 223 patients who received rabies IG, 219 (98%) received doses within 10% of 20 IU/kg of body weight, and all 223 (100%) received rabies IG within 7 days of the first rabies vaccine administration. Only 56% (96 of 170) of patients with a wound that could be infiltrated with rabies IG actually received rabies IG via infiltration into and around the wound. This multi-hospital health system study demonstrated high adherence to guideline recommendations for rabies IG patient selection (91%), dosing (98%), and timing (100%). However, only 56% of eligible patients received rabies IG infiltration at wound sites as recommended by guidelines.

A clear understanding of amyloid formation with diverse morphologies is critical to overcoming the fatal disease amyloidosis. Studies have revealed that monomer concentration is a crucial factor for determining amyloid morphologies, such as protofibrils, annular, or spherical oligomers. However, gaining a complete understanding of the mechanism of formation of the various amyloid morphologies has been limited by the lack of experimental devices and insufficient knowledge. In this study, we demonstrate that the monomer concentration is an essential factor in determining the morphology of beta-amyloid (Aβ) oligomers or protofibrils. By computational and experimental approaches, we investigated the strategies for structural stabilization of amyloid protein, the morphological changes, and amyloid aggregation. In particular, we found unprecedented conformations, e.g., single bent oligomers and segmented ring-shaped protofibrils, the formation of which was explained by the computational analysis. Our findings provide insight into the structural features of amyloid molecules formed at low concentrations of monomer, which will help determine the clinical targets (in therapy) to effectively inhibit amyloid formation in the early stages of the amyloid growth phase.

Circular RNAs (circRNAs) have been reported as effective diagnostic and therapeutic biomarkers in many diseases, but the potential of using this easy-to-monitor and highly stable materials for diagnosing Community-acquired pneumonia (CAP) remains unexplored. Here, aiming to identify potential CAP-related circRNAs in peripheral blood and seeking to deepen the understanding of how circRNA-miRNA-mRNA regulatory networks may contribute to CAP, we applied microarrays profiling analysis and identified 8296 differentially expressed (DE) circRNAs between patients with CAP (n = 6) and healthy controls (n = 6). Subsequently, we validated the accumulation trends for the top 100 DE circRNAs based on qPCR in an independent validation cohort (30 patients vs 30 controls), and ultimately identified a panel of four circRNAs that perform extremely well as sensitive and specific biomarkers for diagnosing CAP: hsa_circ_0018429 (area under the curve [AUC] = 0.8216), hsa_circ_0026579 (AUC = 0.7733), hsa_circ_0125357 (AUC = 0.7730), and hsa_circ_0099188 (AUC = 0.6978); combined as a panel (AUC = 0.8776). In addition, hsa_circ_0026579 exhibited good performance in differentiating viral from bacterial or mixed infection, with an AUC of 0.863. We also identified 10 miRNAs that most likely to interact with these four circRNAs, and then predicted 205 mRNA target genes. The KEGG pathway enrichment analysis suggested highly plausible functional implications related to inflammation and to virus-infection-related signaling pathways (such as HTLV-1 infection and hepatitis B infection). Thus, we generated a genetic network of potential CAP-related regulatory interactions that should inform future hypothesis-driven research into the causes and potential treatment of this widespread and frequently fatal disease.

Cancer despite the introduction of new targeted therapy remains for many patients a fatal disease. Nanotechnology in cancer medicine has emerged as a promising approach to defeat cancer. Targeted delivery of anti-cancer drugs by different nanosystems promises enhanced drug efficacy, selectivity, better safety profile and reduced systemic toxicity. The article presents an overview of recent developments in cancer nanomedicine. We focus on approved anti-cancer medical products and on the results of clinical studies, highlighting that liposomal and micellar cytostatics or albumin-based nanoparticles have less side effects and are more efficient than "free" drugs. In addition, we discuss results of in vitro and in vivo preclinical studies with lipid, inorganic and polymer nanosystems loaded by anticancer drugs which according to our meaning are important for development of new nanodrugs. Pharmacokinetic characteristics of nanodrugs are discussed and characterization of major nanotechnology systems used for cancer nanomedicine is presented.

BackgroundAneurysm of proximal thoracic aorta (pTAA) is an often indolent, yet fatal disease. Although advancements in aneurysmal repair techniques have increased long-term survival rates, studies have proven that there are increases in perioperative risk for stroke incidence after pTAA surgery. Conversely, there is little evidence regarding the long-term stroke incidence in pTAA individuals, which strongly influences the morbidity, mortality, and usage of antithrombotic agents.MethodsUsing the Taiwan National Health Insurance Research Database, a nationwide population-based cohort, we recruited 3013 pTAA survivors hospitalized from 1 January 2000 to 31 December 2012. To ensure study cohort quality, only patients aged 20 years and above who underwent aneurysmal repair surgery are included. The control cohort is identified by matching background features (comorbidities, age, gender) at a 1:4 ratio through the use of frequency matching. The primary outcomes include incidence of ischemic stroke and intracranial hemorrhage one month after aneurysmal repair surgery.ResultsThe mortality of pTAA survivors is nearly twice of the matched controls despite aneurysmal repair (28.5 % vs. 15.2%, p ConclusionsDespite the advancement of aneurysmal repair surgery, this study suggests that pTAA patients may still face an increased risk of hemorrhage stroke. Further investigation is warranted to provide better long-term care for the pTAA population.

Human carbonic anhydrase (hCA) isoenzymes are zinc ion-containing, widespread metalloenzymes and they classically play a role in pH homeostasis maintenance. CA inhibitors suppress the CA activity and their usage has been clinically established as antiglaucoma agents, antiepileptics, diuretics, and in some other disorders. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder and a fatal disease of the brain. An advanced method to cure AD includes the strategy to design acetylcholinesterase (AChE) inhibitors. A novel series of pyrrole-3-one derivatives containing sulfa drugs (5a-i) were determined to be highly potent inhibitors for AChE and hCA I and hCA II (inhibitory constant [Ki ] values are in the range of 6.50 ± 1.02-37.46 ± 4.12 nM, 1.20 ± 0.19-44.21 ± 1.09 nM, and 8.93 ± 1.58-46.86 ± 8.41 nM for AChE, hCA I, and hCA II, respectively). The designed compounds often show a more effective inhibition than the chemicals used as the standard. Among these compounds, 5f was the most effective compound against hCA I, and compound 5e was the most effective compound against hCA II. It was determined that compound 5c was the most effective inhibitor for AChE.

With the global expansion of the highly transmissible SARS-CoV-2 Delta (B.1.617.2) variant, we conducted a matched test-negative case–control study to assess the real-world effectiveness of COVID-19 messenger RNA vaccines against infection with Delta in Qatar’s population. BNT162b2 effectiveness against any, symptomatic or asymptomatic, Delta infection was 45.3% (95% CI, 22.0–61.6%) ≥14 d after the first vaccine dose, but only 51.9% (95% CI, 47.0–56.4%) ≥14 d after the second dose, with 50% of fully vaccinated individuals receiving their second dose before 11 May 2021. Corresponding mRNA-1273 effectiveness ≥14 d after the first or second dose was 73.7% (95% CI, 58.1–83.5%) and 73.1% (95% CI, 67.5–77.8%), respectively. Notably, effectiveness against Delta-induced severe, critical or fatal disease was 93.4% (95% CI, 85.4–97.0%) for BNT162b2 and 96.1% (95% CI, 71.6–99.5%) for mRNA-1273 ≥ 14 d after the second dose. Our findings show robust effectiveness for both BNT162b2 and mRNA-1273 in preventing Delta hospitalization and death in Qatar’s population, despite lower effectiveness in preventing infection, particularly for the BNT162b2 vaccine. mRNA COVID-19 vaccines are highly effective at preventing severe outcomes and death caused by the SARS-CoV-2 Delta variant (B.1.617.2) in Qatar despite substantially lower effectiveness at blocking infection.

The most profound of primary immunodeficiencies, severe combined immunodeficiency (SCID), presents in infancy. Infants appear healthy at birth, but they are unable to clear pathogens, particularly viruses, and present with recurrent infection, progressive pnueumonitis and failure to thrive due to enteric viral infection, often associated with persistent vaccine-strain rotavirus. The administration of live vaccines is contraindicated in these infants, but most who are eligible receive bacillus Calmette–Guérin vaccination and the live rotavirus vaccine before the diagnosis of SCID is made, making treatment more complicated. Newborn infants with SCID can be screened using the newborn bloodspot to measure T lymphocyte receptor excision circles (TRECs), episomal DNA formed during T lymphocyte receptor development and very low or absent in SCID. Introduction of this programme in the United Kingdom will require the neonatal BCG vaccination programme to be altered, with vaccination at 28 days, once the SCID screening result is known. Although SCID newborn screening has been successfully introduced in other countries, the change in neonatal BCG vaccination requires the introduction of newborn screening to be carefully introduced. An evaluation of impact of screening on SCID diagnosis, treatment and outcomes, together with an evaluation of the technology used to detect TRECs, and the impact of screening and changes to the BCG programme on families will commence in six screening regions in England in September 2021 for 2 years – should the evaluation prove positive, it is likely that screening for this fatal disease will be introduced across the United Kingdom.

Background: Primary small cell carcinoma of the esophagus (SCCE) is a rare and extremely fatal disease. We aim to evaluate the efficacy of radical surgery for resectable SCCE and to explore potential prognostic factors. Methods: We retrospectively reviewed 52 consecutive SCCE patients who underwent radical surgery from February 1993 to November 2014 at a single institution. The Kaplan-Meier estimator with log-rank test was used to assess overall survival (OS), disease-free survival (DFS) and median survival time. Univariate and multivariable analyses were used to evaluate prognostic factors through Cox proportional hazard regression model. Results: Twenty-five (48.1%) patients were treated with surgery alone, whereas 27 (51.9%) patients underwent adjuvant therapy after surgery. The median OS time was 17.4 months (95% CI: 13.5-21.3). The median DFS time was 13.4 months (95% CI: 7.7-19.0). Patients whose tumors were located in the lower part of thoracic esophagus and the esophagogastric junction showed significantly better OS (27.0 vs. 13.2 months, P = 0.016) and DFS (27.0 vs. 11.3 months, P = 0.017) than those located in the upper and middle parts. Patients with N0 status experienced significantly better OS (21.4 vs. 11.6 months, P = 0.012) and DFS (21.4 vs. 8.6 months, P = 0.012) than those with N+ status. Patients whose tumor lengths were shorter than 5 cm had a better OS (17.4 vs. 5.7 months, P = 0.035) than those longer than 5 cm. Patients who underwent chemotherapy experienced a significantly improved OS (21.0 vs. 14.1 months, P = 0.032) compared to surgery alone. Multivariable analysis showed that lower tumor location, shorter tumor length, pN0 status and chemotherapy independently predicted better OS; lower tumor location and pN0 status independently predicted better DFS. Conclusions: Radical surgery in combination with chemotherapy has better outcomes than surgery alone for resectable SCCE. Higher tumor location, longer tumor length, lymph node metastasis and not undergoing chemotherapy independently predict worse prognoses.

Background: Esophagogastric junction tumor (EGJ) is a rare but fatal disease with a rapid rising incidence worldwide in the late 20 years, and it lacks a convenient and safe method for diagnosis. The present study aimed to evaluate the potential of serum CYR61 as a biomarker for the diagnosis of EGJ tumor. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to estimate CYR61 levels in sera of 152 EGJ tumor patients and 137 normal controls. Receiver operating characteristics (ROC) was carried out to evaluate the diagnostic accuracy. The Mann–Whitney’s U test was used to compare the difference of serum levels of CYR61 between groups. And chi-square tests were employed to estimate the correlation of the positive rate of serum CYR61 between/among subgroups. Results: Serum CYR61 levels were statistically lower in EGJ tumor and early-stage EGJ tumor patients than those in normal controls (P0.05). Conclusion: The present study showed that CYR61 might be a potential biomarker to assist the diagnosis of EGJ tumor.

Venous thromboembolism (VTE) is a fatal disease and has become a burden on the global health system. Recent studies have suggested that artificial intelligence (AI) could be used to make a diagnosis and predict venous thrombosis more accurately. Thus, we performed a meta-analysis to better evaluate the performance of AI in the prediction and diagnosis of venous thrombosis. PubMed, Web of Science, and EMBASE were used to identify relevant studies. Of the 741 studies, 12 met the inclusion criteria and were included in the meta-analysis. Among them, 5 studies included a training set and test set, and 7 studies included only a training set. In the training set, the pooled sensitivity was 0.87 (95% CI 0.79-0.92), the pooled specificity was 0.95 (95% CI 0.89-0.97), and the area under the summary receiver operating characteristic (SROC) curve was 0.97 (95% CI 0.95-0.98). In the test set, the pooled sensitivity was 0.87 (95% CI 0.74-0.93), the pooled specificity was 0.96 (95% CI 0.79-0.99), and the area under the SROC curve was 0.98 (95% CI 0.97-0.99). The combined results remained significant in the subgroup analyzes, which included venous thrombosis type, AI type, model type (diagnosis/prediction), and whether the period was perioperative. In conclusion, AI may aid in the diagnosis and prediction of venous thrombosis, demonstrating high sensitivity, specificity and area under the SROC curve values. Thus, AI has important clinical value.

This article describes the 6-year journey to diagnosis of twin girls with varying presentations of the same rare disease. Batten disease is a neurodegenerative disease caused by an autosomal recessive genetic mutation. In patients with juvenile Batten disease, the most common initial symptom is vision loss, and initial testing early in the disease process typically fails to find any indication of this fatal disease.

Acute type A aortic dissection is a potentially fatal disease, and emergency surgery should be considered when it is diagnosed. We herein report two cases of retrograde type A aortic dissection with intramural hematoma, followed by re-dissection, rupture, and cardiac tamponade. The diagnoses in these cases had to be made carefully, as the false lumen of the ascending aorta was sometimes unclear on contrast-enhanced computed tomography.

Background: Transthyretin amyloid polyneuropathy (ATTR-PN) is a fatal disease associated with substantial burden of illness. Three therapies are approved by the European Medicines Agency for the management of this rare disease. The aim of this study was to compare the total annual treatment specific cost per-patient associated with ATTR-PN in Spain.Methods: An Excel-based patient burden and cost estimator tool was developed to itemize direct and indirect costs related to treatment with inotersen, patisiran, and tafamidis in the context of ATTR-PN. The product labels and feedback from five Spanish ATTR-PN experts were used to inform resource use and cost inputs.Results: Marked differences in costs were observed between the three therapies. The need for patisiran- and inotersen-treated patients to visit hospitals for pre-treatment, administration, and monitoring was associated with increased patient burden and costs compared to those treated with tafamidis. Drug acquisition costs per-patient per-year were 291,076€ (inotersen), 427,250€ (patisiran) and 129,737€ (tafamidis) and accounted for the majority of total costs. Overall, the total annual per-patient costs were lowest for patients treated with tafamidis (137,954€), followed by inotersen (308,358€), and patisiran (458,771€).Conclusions: Treating patients with tafamidis leads to substantially lower costs and patient burden than with inotersen or patisiran.

Introduction Calciphylaxis is a rare but potentially fatal disease commonly occurred in dialysis patients. Despite some previous studies on risk factors for calciphylaxis, there is still a lack of data from Chinese population. Methods The retrospective matched case–control study about calciphylaxis was performed in Zhongda Hospital affiliated to Southeast University. The case group involved 20 hemodialysis patients who were newly diagnosed with calciphylaxis from October 2017 to December 2018. The 40 noncalciphylaxis patients undergoing dialysis with the same age and duration of dialysis were randomly selected as controls. Results Most of calciphylaxis patients were male and elderly, while overweight people were more susceptible to the disease. Although incidence of secondary hyperparathyroidism was higher in calciphylaxis patients, the differences in duration of elevated serum intact parathyroid hormone (iPTH) and its highest value did not reach statistical significance compared with controls. No significant difference in warfarin therapy was discernible between two groups. The univariate regression analysis indicated that male, score of use of activated vitamin D and its analogues, corrected serum calcium level, serum phosphate, Ca × P product, iPTH, albumin, and alkaline phosphatase (ALP) level were significantly associated with calciphylaxis. Elevated levels of serum phosphate (OR 4.584, p = 0.027) and ALP (OR 1.179, p = 0.036), decreased level of serum albumin (OR 1.330, p = 0.013) were independent risk factors after multivariate analysis. Conclusion This is the first report of risk factors associated with calciphylaxis in China. Increased levels of serum phosphate and ALP, decreased level of serum albumin were vital high-risk factors for calciphylaxis in Chinese hemodialysis population.

Wolfram syndrome is a rare, fatal disease that usually stems from defects in the gene for the protein wolframin. Researchers now have a better understanding of the disease and for the first time are testing potential treatments that might slow its progress. Wolfram syndrome results in symptoms such as blindness, hearing loss, difficulty with movement and coordination, and difficulty breathing. It causes cells throughout the body to die and is usually fatal before the age of 40. Scientists have discovered the disease involves a malfunction by the endoplasmic reticulum called ER stress, and that discovery enabled them to identify several drugs that are now in clinical trials for the illness. Researchers also hope to use genetic engineering and the CRISPR gene-editing tool to correct Wolfram syndrome9s underlying defects. Because ER stress also drives more common illnesses such as Alzheimer9s disease and type 2 diabetes, Wolfram syndrome could also provide insight into the mechanisms of these diseases.

NCR3LG1 (B7-H6) protein is selectively overexpressed on tumour and is associated with fatal disease progression of various cancer. However, its prognostic value in bladder cancer (BCa) has not been well elaborated.We examined the expression of NCR3LG1 in human BCa and analysed its clinical significance and prognostic value. Meanwhile, the expression of NCR3LG1 was intervened in human BCa cell line 253JBV to analyse subsequent effects on tumour.According to TCGA data, the disease-free survival rate was statistically significant between the NCR3LG1 high expression group and the low expression group (Log RankOur findings indicate that NCR3LG1 is involved in the progression of human BCa and may become a potential prognostic biomarker for BCa.

The radiological depiction of posttraumatic pneumocephalus is due to trapped air in most cases. Although rarely reported, it can also be the result of a gas-forming organism, requiring immediate treatment due to high mortality. Here, we report on an elderly patient with radiological appearance of posttraumatic intracranial pneumocephalus after a wound was closed without recognition of a retained tree branch. The piece of wood served as a vector for transmission of Clostridium perfringens causing the collection of abnormal intracranial air. Radical excision of temporal muscle tissue along with extensive evacuation of the brain abscess and targeted intravenous antibiotics resulted in minor morbidity.Although a piece of wood can easily be missed with current diagnostic imaging, it is crucial that both clinicians and radiologists are aware of the presence of air and its differential diagnosis in posttraumatic pneumocephalus, in order to allow timely treatment in this fatal disease.

2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin’s discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin’s role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry’s role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.

Rabies is a highly fatal disease that is endemic in Nigeria. The poor community awareness and knowledge of canine rabies have thwarted the realization of zero deaths from dog mediated human rabies. This study aimed to assess the awareness and knowledge of canine rabies in Kwara state. A total of 1,460 questionnaires were administered to respondents in the three senatorial zones of the state using open data kit (ODK) on mobile phones between September 2019 to January 2020. The rabies awareness rate was 38.1%. The mean knowledge score was 3.78 ± 2.15. Only 10.6% (n = 59/557) of the respondents had satisfactory knowledge of canine rabies. Respondents had poor knowledge of the mode of transmission, symptoms, prevention, and the control measures needed to eliminate canine rabies. Only 20.1% of respondents owned at least a dog. Dog owners were 3.85× (95% CI: 2.89, 5.13; p < 0.01) more likely to be aware of canine rabies and were 1.78× (95% CI: 1.22–2.60; p = 0.003) more likely to have satisfactory knowledge about canine rabies than non-dog owners. Respondents with tertiary education were at least 6.81× (95% CI: 4.24, 10.92; p < 0.01) more likely to be aware of rabies than respondents with no formal education. The findings of this study showed very low awareness and knowledge of canine rabies among residents of Kwara state. Mass sensitization of the populace on the dangers of rabies should be intensified. Such interventions should be targeted at the general public and dog owners.

Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease in which the cause cannot be determined. This article discusses restrictive lung diseases that fall under the general category of interstitial lung disease with a focus on IPF-a fatal disease characterized by progressive fibrosis and interstitial pneumonia, dyspnea, and decreasing pulmonary function.

Alternaria alternata is dematiaceous fungi affecting mainly immunocompromised host. It generally causes cutaneous infection in humans, but can cause fatal disease. Fine needle aspiration cytology (FNAC) has not been used widely for the diagnosis of dematiaceous fungi. Here, we present a case of Alternaria alternata in an immunocompetent patient diagnosed on cytology and culture.

Leishmaniasis is a parasitic morbid/fatal disease caused by Leishmania protozoa. Twelve million people worldwide are appraised to be currently infected, including ca. two million infections each year, and 350 million people in 88 countries are at risk of becoming infected. In Colombia, cutaneous leishmaniasis (CL) is a public health problem in some tropical areas. Therapeutics is based on traditional antileishmanial drugs, but this practice has several drawbacks for patients. Thus, the search for new antileishmanial agents is a serious need, but the lack of adequately funded research programs on drug discovery has hampered its progress. Some Colombian researchers have conducted different research projects focused on the assessment of the antileishmanial activity of naturally occurring and synthetic compounds against promastigotes and/or amastigotes. Results of such studies have separately demonstrated important hits and reasonable potential, but a holistic view of them is lacking. Hence, we present the outcome from a systematic review of the literature (under PRISMA guidelines) on those Colombian studies investigating antileishmanials during the last thirty-two years. In order to combine the general efforts aiming at finding a lead against Leishmania panamensis (one of the most studied and incident parasites in Colombia causing CL) and to recognize structural features of representative compounds, fingerprint-based analyses using conventional machine learning algorithms and clustering methods are shown. Abstraction from such a meta-description led to describe some function-determining molecular features and simplify the clustering of plausible isofunctional hits. This systematic review indicated that the Colombian efforts for the antileishmanials discovery are increasingly intensified, though improvements in the followed pathways must be definitively pursued. In this context, a brief discussion about scope, strengths and limitations of such advances and relationships is addressed.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), a potentially fatal disease, is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The number of cases has increased rapidly, but information on the clinical characteristics remains limited. METHODS: Cohort study. We collected and analyzed epidemiological, demographic, and clinical data of critically and noncritically ill patients and compared the outcomes. RESULTS: The mean age of hospitalized patients with COVID-19 was 54 years (standard deviation 16.9; 53.8% men), 29% required ICU admission, and 18.6% died. CONCLUSIONS: The main risk factors for ICU admission were age over 60 years, obesity, and preexisting chronic lung diseases.

International audience; Cancer is the second most fatal disease in the world and an early diagnosis is important for a successful treatment. Thus, it is necessary to develop fast, sensitive, simple, and inexpensive analytical tools for cancer biomarker detection. MicroRNA (miRNA) is an RNA cancer biomarker where the expression level in body fluid is strongly correlated to cancer. Various biosensors involving the detection of miRNA for cancer diagnosis were developed. The present review o↵ers a comprehensive overview of the recent developments in electrochemical biosensor for miRNA cancer marker detection from 2015 to 2020. The review focuses on the approaches to direct miRNA detection based on the electrochemical signal. It includes a RedOx-labeled probe with di↵erent designs, RedOx DNA-intercalating agents, various kinds of RedOx catalysts used to produce a signal response, and finally a free RedOx indicator. Furthermore, the advantages and drawbacks of these approaches are highlighted.

Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow because of medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment; however, our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited. Methods: We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathological features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexed in situ hybridization, immunostaining, deep confocal imaging, and staged pharmacological inhibition, we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation. Results: Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous, and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension. Conclusions: This work describes the first nongenetically driven murine model of pulmonary hypertension (PH) that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral, and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiological measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.

Background Paraneoplastic pemphigus (PNP) is a rare autoimmune bullous disease classically associated with an underlying neoplasm. The heterogeneous clinical and histopathologic features of the disease make diagnosis challenging for clinicians. There are no formally accepted diagnostic criteria, and newer techniques for identifying antibodies directed against plakin proteins have largely replaced immunoprecipitation, the historic gold standard. Methods An analysis of 265 published cases of PNP was performed. The clinical, histopathologic, and immunologic features of PNP were assessed. Results Based on this review, we modified previous diagnostic criteria to capture 89.4% of PNP cases compared to 71.2% of cases captured by the most commonly referred criteria devised by Camisa and Helm (P-value Conclusion These revised diagnostic criteria address the variable clinical, histopathologic, and biochemical features of PNP, allowing for physicians to have greater confidence in diagnosis of this rare and often fatal disease. The revised criteria include three major criteria and two minor criteria, whereby meeting either all three major criteria or two major and both minor criteria would fulfill a diagnosis of paraneoplastic pemphigus. The major criteria include (1) mucous membrane lesions with or without cutaneous involvement, (2) concomitant internal neoplasm, and (3) serologic evidence of anti-plakin antibodies. The minor criteria include (1) acantholysis and/or lichenoid interface dermatitis on histopathology and (2) direct immunofluorescence staining showing intercellular and/or basement membrane staining. This article is protected by copyright. All rights reserved.

More than a century separates the description of “dropsy of the ventricles of the brain” by Scottish physicians and Robert Koch’s identification of the causal agent of tuberculous meningitis in 1882. This article reviews the writings in Scotland and France that marked the history of the identification of this infectious entity. From John Paisley in 1734 to Robert Whytt in 1738, from Marcellin Chardel in 1799 and L.P. Collinet in 1802 to Isidore Bricheteau in 1814 and Jean-Louis Brachet in 1818, and then Victor Le Diberder in 1837 and Isidore Valleix in 1838, unknown and forgotten physicians outnumber the famous masters in bringing about the progress and knowledge that enabled this frequent and consistently fatal disease in the 19th century to be accurately diagnosed and in most cases cured in the 20th century.

The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal fluid. Substantial evolution occurs within the prostate, resulting in branching into multiple spatially intermixed lineages. One dominant lineage emerges that initiates and drives systemic metastasis, where polyclonal seeding between sites is common. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains confined to the prostate within each patient. Body fluids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal fluid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility., The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. Here, the authors use deep genomic sequencing and histopathological information to trace tumor evolution both within the prostate and during metastasis in ten men.