Rapid screening of bacteriostatic and bactericidal antimicrobial agents against Escherichia coli by combining machine learning (artificial intelligence) and UV-VIS spectroscopy.

Antibiotics are compounds that have a particular mode of action upon the microorganism they are targeting. However, discovering and developing new antibiotics is a challenging and timely process. Antibiotic development process can take up to 10-15 years and over $1billion to develop a single new therapeutic product. Rapid screening tools to understand the mode of action of the new antimicrobial agent are considered one of the main bottle necks in the antimicrobial agent development process. Classical approaches require multifarious microbiological methods and they do not capture important biochemical and organism therapeutic-interaction mechanisms. This work aims to provide a rapid antibiotic-antimicrobial biochemical diagnostic tool to reduce the timeframes of therapeutic development, while also generating new biochemical insight into an antimicrobial-therapeutic screening assay in a complex matrix. The work evaluates the effect of antimicrobial action through "traditional" microbiological analysis techniques with a high-throughput rapid analysis method using UV-VIS spectroscopy and chemometrics. Bacteriostatic activity from tetracycline and bactericidal activity from amoxicillin were evaluated on a system using non-resistant Escherichia coli O157:H7 by confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM), and UV-VIS spectroscopy (high-throughput analysis). The data were analysed using principal component analysis (PCA) and support vector machine (SVM) classification. The rapid diagnostic technique could easily identify differences between bacteriostatic and bactericidal mechanisms and was considerably quicker than the "traditional" methods tested.

A study of non small cell lung cancer (NSCLC) patients with brain metastasis: A single centre experience.

BACKGROUND: Lung cancer is the leading cause of cancer death with the majority of cases being non-small cell lung cancer (NSCLC) [1]. A common complication of NSCLC is brain metastasis (BM) [2, 3], where the prognosis remains poor despite new treatments. Real world data complements data gained from clinical trials, providing information on patients excluded from prospective research [4]. However, information from patient notes may prove incomplete and difficult to extract. We developed an algorithm to identify patients in our clinical database with brain metastasis from the electronic health record (EHR). METHODS: We retrospectively extracted data from the EHR of patients managed at a large teaching hospital between 2007 and 2018. Using the ICD-10 code C34, for lung cancer, our algorithm used phrases associated with BMs to search the unstructured text of radiology reports. Summary statistics and univariant analysis was performed for overall survival. RESULTS: 818 patients were identified as potentially having BM and 453 patients were confirmed on clinical review of their records. The median age of patients was 69 years, 50% were female and 66% had a performance status of >2. 12.2% had an identifiable mutation and 11.5% were identified as PD-L1 positive. In the first line setting, 65% of patients received symptomatic treatment, 23% received systemic anticancer therapy (SACT), 6.1% surgery and 10% radiotherapy, of which 6.5% had external beam and 3.5% stereotactic radiosurgery. Regarding those treated with SACT, 35% had an intracranial response to treatment (3% had complete response, 32% had a partial response). Median survival was 2 months (1.9 - 2.4 months 95% CI). CONCLUSION: The real-world prognosis for NSCLC patients with BMs is poor. By using an algorithm, we have reported outcomes on a comprehensive cohort of patients which helps identify those for whom an active treatment approach is appropriate.

A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO).

BACKGROUND: Elderly patients are commonly under-represented in cancer clinical trials. The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and/or elderly population with advanced gastroesophageal (GO) cancer. METHODS: Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were randomly assigned in a 1 : 1 : 1 ratio to: epirubicin, oxaliplatin and capecitabine (EOX); oxaliplatin and capecitabine (OX); and capecitabine alone (X) (all 80% of full dose and unblinded). The primary end point was patient recruitment over an 18-month period. A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres. RESULTS: A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period: 115 received full dose treatment, 89 less than standard treatment or entered 321GO and 111 no treatment. Within 321GO, 55 patients were randomly assigned (19 to OX and X; 17 to EOX). Progression-free survival (PFS) for all patients was 4.4 months and by arm 5.4, 5.6 and 3.0 months for EOX, OX and X, respectively. The number of patients with a good overall treatment utility (OTU), a novel patient-centred endpoint, at 12 weeks was 3 (18%), 6 (32%) and 1 (6%) for EOX, OX and X, respectively. At 6 weeks, 22 patients (41%) had experienced a non-haematologic toxicity ⩾grade 3, most commonly lethargy or diarrhoea. The OTU was prognostic for overall survival in patients alive at week 12 (logrank test P=0.0001). CONCLUSIONS: It is feasible to recruit elderly and/or frail patients with advanced GO cancer to a randomised clinical trial. The OX is the preferred regimen for further study. Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and randomised trials in the elderly and/or frail GO cancer population.

Regulation and registration as drivers of continuous professional competence for Irish pre-hospital practitioners: a discussion paper.

BACKGROUND: The regulatory body responsible for the registration of Irish pre-hospital practitioners, the Pre-Hospital Emergency Care Council (PHECC), identified the need to implement a continuing professional competence (CPC) framework. The first cycle of CPC (focused on emergency medical technicians) commenced in November 2013 creating for the first time a formal relationship between continuing competence and registration to practice. AIMS: To review current literature and to describe benefits and challenges relevant to CPC, regulation, registration and their respective contributions to professionalism of pre-hospital practitioners: advanced paramedics, paramedics and emergency medical technicians. METHODS: Online search of cumulative index to nursing and allied health literature (CINAHL Plus with Full Text), Allied and Complementary Medicine (AMED) and 'Pubmed' databases using: 'Continuous Professional Development'; 'Continuous Professional Development'; 'emergency medical technician'; 'paramedic'; 'registration'; 'regulation'; and "profession' for relevant articles published since 2004. Additional policy documents, discussion papers, and guidance documents were identified from bibliographies of papers found. RESULTS: Reports, governmental policies for other healthcare professions, and professional developments internationally for allied professions (e.g., nursing, physiotherapy and medicine) link maintenance of competence with requirements for registration to practice. CONCLUSION: We suggest that evolving professionalisation of Irish paramedics should be affirmed through behaviours and competencies that incorporate adherence to professional codes of conduct, reflective practice, and commitment to continuing professional development. While the need for ambulance practitioner CPD was identified in Ireland almost a decade ago, PHECC now has the opportunity to introduce a model of CPD for paramedics linking competence and professionalism to annual registration.

A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer.

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified 'Modified de Gramont' (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m(-2)), then ambulatory 46-h fluorouracil infusion (2000-3600 mg m(-2), cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m(-2). Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m(-2) bolus + 2800 mg m(-2) 46-h infusion. A lower dose of 400 mg m(-2) bolus + 2400 mg m(-2) infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC(0-48 h)) at this lower dose is equivalent to dG. With OxMdG, grade 3-4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea <1% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. MdG and OxMdG are convenient and well-tolerated. OxMdG was particularly active as 1st-line treatment of advanced colorectal cancer. Both regimens are being further evaluated in the current UK MRC phase III trial.

Caelyx (stealth liposomal doxorubicin) in the treatment of advanced breast cancer.

Anthracyclines are amongst the most active drugs in the treatment of breast cancer. Stealth liposomal doxorubicin (Caelyx, Doxil, Alza Pharmaceuticals Inc.) is a promising new agent under investigation for the treatment of breast cancer and other solid tumours. The liposomal encapsulation alters drug pharmacokinetics and leads to a marked change in toxicity profile compared to non-liposomal doxorubicin. The results of recently completed and ongoing clinical trials in breast cancer are reviewed.

Influenza and HIV: case report and review of potential interactions.

We describe a patient with AIDS who required hospitalization for influenza A. We review the classic pulmonary complications of influenza as seen in patients with HIV infection and discuss the clinical features, differential diagnosis, laboratory diagnosis, treatment, and prevention of influenza in this setting.

Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours.

CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C(max)and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C(max)and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V(d)and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m(2)because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m(2)daily x 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination.

Influenza in human immunodeficiency virus-infected patients during the 1997-1998 influenza season.

A cluster of cases of severe influenzal disease was recognized in HIV-infected individuals during the 1997-1998 influenza season. Both primary influenza pneumonia and concomitant viral and bacterial pneumonia were found.

Bulleidia extructa gen. nov., sp. nov., isolated from the oral cavity.

Five strains of anaerobic non-sporing Gram-positive bacilli isolated from advanced periodontitis (four strains) and a dentoalveolar abscess (one strain) that did not correspond to existing species were subjected to phenotypic and genetic characterization. Following 16S rDNA sequence analysis, they were found to constitute a novel branch of the low G+C Gram-positive division of the phylogenetic tree related to Erysipelothrix rhusiopathiae and Holdemania filiformis. A new genus Bulleidia, and the species Bulleidia extructa, are proposed. Growth of B. extructa in broth media was poor but was enhanced by the addition of fructose, glucose or maltose together with Tween 80. Glucose and maltose were fermented and arginine was hydrolysed. Acetate, lactate and trace amounts of succinate were the end products of glucose fermentation. The G+C content of the DNA of the type strain is 38 mol%. The type strain of Bulleidia extructa is DSM 13220T.

Phase II study of oral topotecan in advanced non-small cell lung cancer.

This study was designed to assess the activity of oral topotecan (TPT) in patients with advanced non-small cell lung cancer previously untreated with chemotherapy. Eligible patients had inoperable stage III or stage IV non-small cell lung cancer and were chemotherapy-naive. Other inclusion criteria were Eastern Cooperative Oncology Group performance status 0, 1, or 2, adequate bone marrow, and renal and hepatic function. Of 30 patients, 29 were assessable for response. Oral TPT was administered for 5 days every 21 days for up to six cycles unless disease progression or unacceptable toxicity occurred. Patients received a dose of 2.3 mg/m2/day for the first cycle. Dose modification for subsequent cycles was based on tolerability. Patients completed symptom questionnaires every 3 weeks. Pharmacokinetics were evaluated in all patients during cycle 1. Three patients had radiological responses with a reduction in tumor size of 30-40%. No patients achieved complete or partial responses to treatment. Thirteen patients had a stable disease (43.3%), and the median survival was 39.9 weeks with a 1-year survival of 33.3%. At the time of analysis, 27 patients had died. Median time to progression was 12.3 weeks. Treatment was well tolerated. A total of 125 cycles of treatment were completed. Twelve patients (40%) experienced grade III/IV neutropenia. Five patients (16.6%) had grade III/IV anemia. There were two episodes of grade III/IV thrombocytopenia. The main nonhematological toxicities consisted of grade III nausea (13%) and grade III vomiting (13%). The most frequently reported disease-related symptoms at baseline were dyspnea, cough, and fatigue. There was a subsequent improvement in patient scores of dyspnea in 17% of patients, 31% showed improvement in cough, and 32% showed improvement in fatigue. The mean area under the curve of TPT following 2.3 mg/m2 p.o. was 51.6 ng.h/ml (%SD, 25%). The area under the curve of TPT on day 1 of the first cycle was correlated with the percentage fall in leukocytes. Although oral TPT at the applied dose and schedule showed modest activity as a single agent, almost one-half of the patients had a stable disease, and median time to progression was 12.3 weeks. The overall median survival was a promising 39.9 weeks, and useful palliation of symptoms was seen.

Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy.

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.

Cerebral metastases in malignant mesothelioma: a case report.

A case of a 61-year-old man with metastatic malignant mesothelioma is described. Four months after diagnosis the patient commenced chemotherapy with liposomal doxorubicin as part of an EORTC phase II trial. He developed signs of intracerebral metastases after his fourth cycle of chemotherapy and died shortly after. Malignant mesothelioma is traditionally viewed as a disease that spreads locally but metastasizes rarely. We describe in detail this case and suggest that metastases in this disease are not as uncommon as originally proposed.

Development and validation of a sensitive solid-phase extraction and high-performance liquid chromatography assay for the novel antitumour agent CT2584 in human plasma.

A HPLC assay and solid-phase extraction technique from human plasma has been developed and validated for the novel anticancer agent CT2584, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, which has recently completed a phase I trial at the Christie Hospital, Manchester under the auspices of the CRC phase I/II committee. Following addition of CT2576, 1-(11-octylamino-10-hydroxylundecyl)-3,7-dimethylxanthine, as internal standard, a solid-phase extraction cartridge (100 mg cyanopropyl) was used to isolate the drug CT2584 from human plasma. Analysis was performed by reversed-phase chromatography. CT2576 was used as internal standard at a concentration of 4 microg ml(-1) for the quantification of CT2584 from plasma for the duration of this work. The lower limit of quantification for the drug CT2584 in buffer using this assay was found to be 0.0122 microM (0.008 microg ml(-1)) and 0.048 microM (0.027 microg ml(-1)) when extracted from human plasma.

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Multiple prosthodontic uses for permanent crown remover forceps.

Practitioners will find multiple uses for Perm Gripper forceps. These crown remover forceps are likely to become an indispensable adjunct in the busy prosthodontic practice.

Phylogeny of oral asaccharolytic Eubacterium species determined by 16S ribosomal DNA sequence comparison and proposal of Eubacterium infirmum sp. nov. and Eubacterium tardum sp. nov.

16S rRNA gene sequences of Eubacterium brachy, Eubacterium nodatum, Eubacterium saphenum, Eubacterium timidum, and two previously unnamed taxa were determined. The results of a phylogenetic analysis indicated that all of the strains sequenced belonged to a deep branch of the low-G+C-content gram-positive group. The levels of 16S ribosomal DNA sequence similarity between species were low, suggesting that a number of genera may be represented in this group. The representatives of the two unnamed taxa, which were isolated from patients with periodontitis, were clearly distinct from the previously described species, and, therefore, the following two new species are proposed: Eubacterium infirmum (type strain, NCTC 12940) and Eubacterium tardum (type strain, NCTC 12941).

Ovarian Burkitt lymphoma: pelvic pain in a woman with AIDS.

BACKGROUND: Non-Hodgkin lymphomas, a common AIDS-defining manifestation of human immunodeficiency virus (HIV), are aggressive, advanced at diagnosis, and tend to involve extranodal sites. Burkitt lymphoma comprises approximately 20% of AIDS-related non-Hodgkin lymphomas. Sites frequently affected by the disease include the central nervous system, bone marrow, gastrointestinal tract, and mucocutaneous tissue. Gonadal involvement is less common; reports of testicular lymphomas in adult males with AIDS have been sporadic. Ovarian involvement in AIDS-related lymphoma is exceedingly rare and usually involves pediatric patients. CASE: We report an unusual case in which disseminated Burkitt lymphoma presented as pelvic pain in a 32-year-old woman with AIDS. At laparoscopy, the ovaries were unremarkable in appearance but at the upper limits of normal size. However, extreme friability of the left ovary led to hemorrhage and oophorectomy. Pathologic evaluation of the ovary resulted in the diagnosis of Burkitt lymphoma. CONCLUSION: With improved survival because of antiretroviral therapy, the incidence of AIDS-related lymphomas is expected to rise. Lymphoma should be considered in the differential diagnosis of women with AIDS with perplexing abdominal or pelvic symptoms.