Supervised machine learning for the prediction of infection on admission to hospital: a prospective observational cohort study.

BACKGROUND: Infection diagnosis can be challenging, relying on clinical judgement and non-specific markers of infection. We evaluated a supervised machine learning (SML) algorithm for diagnosing bacterial infection using routinely available blood parameters on presentation to hospital. METHODS: An SML algorithm was developed to classify cases into infection versus no infection using microbiology records and six available blood parameters (C-reactive protein, white cell count, bilirubin, creatinine, ALT and alkaline phosphatase) from 160203 individuals. A cohort of patients admitted to hospital over a 6 month period had their admission blood parameters prospectively inputted into the SML algorithm. They were prospectively followed up from admission to classify those who fulfilled clinical case criteria for a community-acquired bacterial infection within 72 h of admission using a pre-determined definition. Predictive ability was assessed using receiver operating characteristics (ROC) with cut-off values for optimal sensitivity and specificity explored. RESULTS: One hundred and four individuals were included prospectively. The median (range) cohort age was 65 (21-98) years. The majority were female (56/104; 54%). Thirty-six (35%) were diagnosed with infection in the first 72 h of admission. Overall, 44/104 (42%) individuals had microbiological investigations performed. Treatment was prescribed for 33/36 (92%) of infected individuals and 4/68 (6%) of those with no identifiable bacterial infection. Mean (SD) likelihood estimates for those with and without infection were significantly different. The infection group had a likelihood of 0.80 (0.09) and the non-infection group 0.50 (0.29) (P < 0.01; 95% CI: 0.20-0.40). ROC AUC was 0.84 (95% CI: 0.76-0.91). CONCLUSIONS: An SML algorithm was able to diagnose infection in individuals presenting to hospital using routinely available blood parameters.

Delivering precision antimicrobial therapy through closed-loop control systems.

Sub-optimal exposure to antimicrobial therapy is associated with poor patient outcomes and the development of antimicrobial resistance. Mechanisms for optimizing the concentration of a drug within the individual patient are under development. However, several barriers remain in realizing true individualization of therapy. These include problems with plasma drug sampling, availability of appropriate assays, and current mechanisms for dose adjustment. Biosensor technology offers a means of providing real-time monitoring of antimicrobials in a minimally invasive fashion. We report the potential for using microneedle biosensor technology as part of closed-loop control systems for the optimization of antimicrobial therapy in individual patients.

Ventral colporectopexy for overt rectal prolapse and obstructed defaecation syndrome: a systematic review.

AIM: Laparoscopic ventral rectopexy (VR) with the use of prosthesis has been advocated for both overt rectal prolapse (ORP) and obstructed defaecation syndrome (ODS). The present study reviews the short-term and functional results of laparoscopic VR. METHOD: A search was performed of MEDLINE, EMBASE, Ovid and Cochrane databases on all studies reporting on VR for ORP, ODS and other anatomical abnormalities of the pelvic floor from 2004 until February 2013. No language restrictions were made. All studies on VR were reviewed systematically. The main outcomes were intra-operative complications, conversion, procedure duration, short-term mortality and morbidity, length of stay, recurrence of ORP, recurrence of anatomical disorder, faecal incontinence and constipation, quality of life (QoL) score and patient satisfaction. Quality assessment and data extraction were performed independently by three observers. RESULTS: Twenty-three studies including 1460 patients were eligible for analysis. The conversion rate ranged from 0 to 14.3%. No mortality was reported. The immediate postoperative morbidity rate was 8.6%. Length of stay ranged from 1 to 7 days. A significant improvement in constipation and incontinence symptoms was observed in the postoperative period for both ORP and ODS (chi-square test, P < 0.0001). CONCLUSION: Laparoscopic VR is a safe and effective procedure for ORP and ODS. Longer follow-up is required, and studies comparing VR with standard rectopexy and stapled transanal rectal resection are not yet available.

Learning curve for the management of recurrent and locally advanced primary rectal cancer: a single team's experience.

AIM: The study aimed to define the learning curve required to gain satisfactory training to perform pelvic exenterative surgery for recurrent or locally advanced primary rectal cancer. METHOD: Consecutive patients undergoing exenterative pelvic surgery for recurrent and locally advanced primary rectal cancer, by one surgical team, between 2006 and 2011 were studied. They were divided into quartiles (Q1-Q4) according to the date of surgery. A risk-adjusted cumulative sum (RA-CUSUM) model was used to evaluate the learning curve. The chi-squared test with gamma ordinal was used to assess the change with time in the four quartiles. RESULTS: One hundred patients (70 males; median age 61 (25-85) years; 55 primary cancers) were included in the study. Thirty patients underwent abdominosacral resection. The number of patients who underwent plastic reconstruction (n = 53) increased from 12 in Q1 to 15 in Q4 (P = 0.781). The median operation time, intra-operative blood loss and hospital stay were 8 (3-17) h, 1.5 (0.1-17) l and 15 (9-82) days respectively. There was no significant change with time. Complete resection (R0) was achieved in 78 patients. Microscopic (R1) or macroscopic (R2) residual disease was present in 15 and seven patients respectively. The number of major complications was 20, and minor 30. RA-CUSUM analysis demonstrated an improvement in any complications after 14, in major after 12 and in minor after 25 operations. CONCLUSION: Pelvic exenterative surgery for recurrent or locally advanced primary rectal cancer is complex and requires a minimum of 14 cases for an expert colorectal surgeon to gain the desirable training and experience to improve morbidity.

Is robotic ventral mesh rectopexy better than laparoscopy in the treatment of rectal prolapse and obstructed defecation? A meta-analysis.

Ventral mesh rectopexy is an approach in the treatment of internal and external rectal prolapse and rectocele. Our aim was to assess whether robotic surgery confers any significant advantages over laparoscopy, and the associated complication rate. Two reviewers performed a literature search using MEDLINE and PubMed databases for studies comparing robotic versus laparoscopic surgery. Five prospective, non-randomised studies were identified and included. A total of 244 patients (101 robotic and 143 laparoscopic) were included in the analysis. Operative time was shorter with laparoscopic surgery, mean weighted difference 27.94 [confidence interval (CI) 19.30-36.57; p < 0.00001]. The conversion rate was not significantly different between groups. There was a trend towards a reduction in length of inpatient stay and early post-operative complications in the robotic group; however, these did not reach statistical significance. Recurrence rates were similar between groups (odds ratio 0.91, CI 0.32-2.63; p = 0.87). Functional results were comparable between groups. Early studies show that robotic ventral rectopexy is a safe option compared to the laparoscopic approach, with overall comparable results. There appeared to be a trend towards a reduction in length of inpatient stay and post-operative complications. These perceived benefits may offset the longer operative times and outlay costs. Larger randomised controlled trials are needed to further evaluate clinical value and cost-effectiveness.

Machine learning for clinical decision support in infectious diseases: a narrative review of current applications.

BACKGROUND: Machine learning (ML) is a growing field in medicine. This narrative review describes the current body of literature on ML for clinical decision support in infectious diseases (ID). OBJECTIVES: We aim to inform clinicians about the use of ML for diagnosis, classification, outcome prediction and antimicrobial management in ID. SOURCES: References for this review were identified through searches of MEDLINE/PubMed, EMBASE, Google Scholar, biorXiv, ACM Digital Library, arXiV and IEEE Xplore Digital Library up to July 2019. CONTENT: We found 60 unique ML-clinical decision support systems (ML-CDSS) aiming to assist ID clinicians. Overall, 37 (62%) focused on bacterial infections, 10 (17%) on viral infections, nine (15%) on tuberculosis and four (7%) on any kind of infection. Among them, 20 (33%) addressed the diagnosis of infection, 18 (30%) the prediction, early detection or stratification of sepsis, 13 (22%) the prediction of treatment response, four (7%) the prediction of antibiotic resistance, three (5%) the choice of antibiotic regimen and two (3%) the choice of a combination antiretroviral therapy. The ML-CDSS were developed for intensive care units (n = 24, 40%), ID consultation (n = 15, 25%), medical or surgical wards (n = 13, 20%), emergency department (n = 4, 7%), primary care (n = 3, 5%) and antimicrobial stewardship (n = 1, 2%). Fifty-three ML-CDSS (88%) were developed using data from high-income countries and seven (12%) with data from low- and middle-income countries (LMIC). The evaluation of ML-CDSS was limited to measures of performance (e.g. sensitivity, specificity) for 57 ML-CDSS (95%) and included data in clinical practice for three (5%). IMPLICATIONS: Considering comprehensive patient data from socioeconomically diverse healthcare settings, including primary care and LMICs, may improve the ability of ML-CDSS to suggest decisions adapted to various clinical contexts. Currents gaps identified in the evaluation of ML-CDSS must also be addressed in order to know the potential impact of such tools for clinicians and patients.

A fatal case of cutaneous zygomycosis in a patient with severe metabolic acidosis.

We present a case of cutaneous zygomycosis in a patient with an ureteroileostomy and severe metabolic acidosis, but without diabetes. The patient died despite multiple aggressive surgical interventions and antifungal therapy with liposomal amphotericin B. Ureteroileostomy-related acidosis can be a predisposing factor for zygomycosis. Metabolic acidosis can have a role in the severity of cutaneous disease.

A systematic review of clinical decision support systems for antimicrobial management: are we failing to investigate these interventions appropriately?

OBJECTIVES: Clinical decision support systems (CDSS) for antimicrobial management can support clinicians to optimize antimicrobial therapy. We reviewed all original literature (qualitative and quantitative) to understand the current scope of CDSS for antimicrobial management and analyse existing methods used to evaluate and report such systems. METHOD: PRISMA guidelines were followed. Medline, EMBASE, HMIC Health and Management and Global Health databases were searched from 1 January 1980 to 31 October 2015. All primary research studies describing CDSS for antimicrobial management in adults in primary or secondary care were included. For qualitative studies, thematic synthesis was performed. Quality was assessed using Integrated quality Criteria for the Review Of Multiple Study designs (ICROMS) criteria. CDSS reporting was assessed against a reporting framework for behaviour change intervention implementation. RESULTS: Fifty-eight original articles were included describing 38 independent CDSS. The majority of systems target antimicrobial prescribing (29/38;76%), are platforms integrated with electronic medical records (28/38;74%), and have a rules-based infrastructure providing decision support (29/38;76%). On evaluation against the intervention reporting framework, CDSS studies fail to report consideration of the non-expert, end-user workflow. They have narrow focus, such as antimicrobial selection, and use proxy outcome measures. Engagement with CDSS by clinicians was poor. CONCLUSION: Greater consideration of the factors that drive non-expert decision making must be considered when designing CDSS interventions. Future work must aim to expand CDSS beyond simply selecting appropriate antimicrobials with clear and systematic reporting frameworks for CDSS interventions developed to address current gaps identified in the reporting of evidence.

Beam distortion due to gold fiducial markers during salvage high-intensity focused ultrasound in the prostate.

PURPOSE: High intensity focused ultrasound (HIFU) provides a non-invasive salvage treatment option for patients with recurrence after external beam radiation therapy (EBRT). As part of EBRT the prostate is frequently implanted with permanent fiducial markers. To date, the impact of these markers on subsequent HIFU treatment is unknown. The objective of this work was to systematically investigate, using computational simulations, how these fiducial markers affect the delivery of HIFU treatment. METHODS: A series of simulations was performed modelling the propagation of ultrasound pressure waves in the prostate with a single spherical or cylindrical gold marker at different positions and orientations. For each marker configuration, a set of metrics (spatial-peak temporal-average intensity, focus shift, focal volume) was evaluated to quantify the distortion introduced at the focus. An analytical model was also developed describing the marker effect on the intensity at the focus. The model was used to examine the marker's impact in a clinical setting through case studies. RESULTS: The simulations show that the presence of the marker in the pre-focal region causes reflections which induce a decrease in the focal intensity and focal volume, and a shift of the maximum pressure point away from the transducer's focus. These effects depend on the shape and orientation of the marker and become more pronounced as its distance from the transducer's focus decreases, with the distortion introduced by the marker greatly increasing when placed within 5 mm of the focus. The analytical model approximates the marker's effect and can be used as an alternative method to the computationally intensive and time consuming simulations for quickly estimating the intensity at the focus. A retrospective review of a small patient cohort selected for focal HIFU after failed EBRT indicates that the presence of the marker may affect HIFU treatment delivery. CONCLUSIONS: The distortion introduced by the marker to the HIFU beam when positioned close to the focus may result in an undertreated region beyond the marker due to less energy arriving at the focus, and an overtreated region due to reflections. Further work is necessary to investigate whether the results presented here justify the revision of the patient selection criteria or the markers' placement protocol.

Animal models to improve our understanding and treatment of suicidal behavior.

Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic-pituitary-adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio.

Autoantibodies against aggrecan in systemic rheumatic diseases.

OBJECTIVE: This study was undertaken to investigate the presence of autoantibodies against the main cartilage proteoglycan, aggrecan, in systemic rheumatic disease sera, and to identify substructure(s) responsible for the autoimmune response. METHODS: Sera were obtained from 86 patients with various systemic rheumatic diseases, 14 with osteoarthritis (OA), 18 with cancer and 40 healthy individuals. The presence of autoantibodies against aggrecan was examined by a solid phase assay and by Western blotting, using proteoglycan aggregates treated with proteolytic enzymes. The positive bands were subjected to nanohigh performance liquid chromatography (nanoHPLC)-MS, in order to identify the aggrecan substructures involved in the autoimmune response. RESULTS: Autoantibodies against aggrecan were identified in all systemic rheumatic disease sera at a high titre, almost three times that observed in healthy controls. OA and cancer sera produced a reaction equal to that of the healthy. Western blotting analysis of aggrecan proteolytic fragments revealed the presence of a triple band, reacting with the patients' sera, of about 37 kDa, which also reacted with a polyclonal antibody against hyaluronan-binding region. NanoHPLC-MS analysis suggested that this band belonged to the G2 domain of aggrecan. CONCLUSION: At least a part of the autoimmune reaction to aggrecan, displayed by the systemic disease sera, involves the G2 domain. The significant difference observed between these sera and those from other diseases, especially cancer, may suggest a possible discriminatory role of anti-aggrecan antibodies. This may help in the differential diagnosis in complicated clinical cases. However, for this to be confirmed, studies in larger cohorts of patients should be performed.

Reconstructive surgery for kidney transplant recipients.

Many decades have passed since the first kidney transplantation, which is now the most common organ transplant performed worldwide. Despite the impressive advances, some patients may develop posttransplant complications that require proper management and treatment. The plastic and reconstructive surgeon, among others, may be called on to help resolve a number of reconstructive problems present in the immunosuppressed kidney recipients. This study presents our experience with 41 kidney recipients who needed plastic surgical treatment. Patients were placed into one of three study groups according to the type of posttransplant surgical condition. Group 1 included 17 patients with posttraumatic wound healing problems; group 2, 17 patients with skin tumors; and group 3, 7 patients with other posttransplant surgical complications. Only two of these patients had early posttransplant wound dehiscence; the remaining patients suffered late complications. In conclusion, the kidney recipient can successfully undergo minor or major reconstructive procedures. The possibility of surgical problems arising during the early posttransplant period presents increased complication rates, possibly due to high immunosuppressive drug levels.

Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.

INTRODUCTION: The real life effectiveness, safety and the use of omalizumab for Portuguese patients with uncontrolled persistent allergic asthma are not sufficiently well known. The objective of this report was to make an evaluation, in a post-marketing, non-interventional, observational registry, of the Portuguese population included in the eXpeRience study. METHODS: The methods used in this report are the same as the global eXpeRience ones, applied to a Portuguese sub-population. Patients with uncontrolled allergic asthma who had started omalizumab within the previous 15 weeks were enrolled and received omalizumab add-on therapy for 24 months. The physicians' global evaluation of treatment effectiveness (GETE), asthma symptoms and control (ACT score), quality of life (mini-AQLQ score), exacerbations, and serious adverse events (SAE) were reported. RESULTS: Of the 943 patients recruited in the eXpeRience registry, 62 patients were from Portugal. 62.1% of them were observed to be responders with good/excellent GETE assessment at Week 16. Clinically meaningful improvements in asthma control (ACT score) and quality of life (mini-AQLQ score) were observed with omalizumab therapy at Months 12 (mean change: +7.7 [n=35]; +2.1 [n=20], respectively) and 24 (mean change: +7.0 [n=26]; +2.7 [n=13], respectively). Asthma symptoms and rescue medication usage were reduced to ≤1 day/week at Month 24 from a baseline of ≥3.5 days/week. The proportion of patients with no clinically significant exacerbations increased from 6.5% during pre-treatment (n=62) to 50% at Month 12 (n=54) and 60% at Month 24 (n=45). CONCLUSION: The findings from the Portugal subpopulation of eXpeRience registry confirm that omalizumab add-on therapy is efficacious and well tolerated in the management of uncontrolled persistent allergic asthma. Another pertinent issue is the fact that the Portuguese subpopulation response is similar to the international population average of the study.

An electrophysiologic study of rabbit ciliary epithelium.

Microelectrode recordings from cells in rabbit ciliary epithelium have been made in vitro. Ionophoresis of Lucifer Yellow dye from microelectrodes during measurements of potential confirmed that the recordings were intracellular. Dye passed from the impaled cells into adjacent cells in both the nonpigmented and pigmented layers of the epithelium. Electrical coupling between epithelial cells also was observed. The mean (+/- SD) values of the potential measured across the basolateral membranes of the nonpigmented cells was -65 +/- -15 mV (n = 77); the mean value of the input resistance at this intracellular recording site was 37 +/- 28 M omega (n = 17). The membrane potential was reduced by raising the concentration of extracellular potassium but unaffected by changes in the concentrations of sodium, chloride, or bicarbonate ions. After a period of deprivation of extracellular potassium, the cells hyperpolarized without a measurable change in membrane resistance when potassium was restored to the bathing solution; this transient response to potassium was abolished by preincubation with ouabain or by bathing the epithelium in a solution lacking sodium. It was concluded that the ciliary epithelial cells are permeable to potassium but exhibit only a low permeability to sodium, chloride, or bicarbonate ions; that the cells possess an electrogenic Na/K pump; and finally, that all of the cells in the epithelium function as a syncytium.

Characterization of ectopically-expressed ets1 in human colon-cancer cells - induction of putative ets1-target gene.

We have previously shown that the ETS1 gene is expressed in a tissue-specific manner, and encodes a transcription factor, that may be involved in lymphocyte development, activation and proliferation. To understand the ETS1 function in non-lymphoid cells, we have ectopically expressed ETS1 protein in a human colon cancer cell line, and studied its biochemical properties. The 51 kDa ETS1 protein expressed in transfected cells localized in both the nucleus and the cytoplasm, has similar biochemical properties compared to ETS1 protein expressed in lymphoid cells. The ectopically expressed ETS1 binds to the DNA in sequence-specific manner and the binding activity is affected by the flanking sequences outside the 'GGA' core. Our results also demonstrate that the DNA-binding activity of full-length ETS1 is similar in lymphoid and non-lymphoid cells. The ETS1 expressed in DLD-1 cells is biologically active since it induces a 54.5 kDa polypeptide, whose expression level correlates with the expression of ETS1 in DLD-1 cells.

Expression of ets family genes in hematopoietic-cells.

We have examined the expression of the ets family of transcription factors in different types of hematopoietic cells. Our results demonstrate that several members of the ets gene family are expressed differentially in hematopoietic cells. During phorbol ester induced differentiation of HL60 cells, ETS2, PEA3, as well as GABPalpha and GABPbeta mRNAs are coordinately induced. During the activation of T-cells, ETS2 proteins are induced; however, the expression of the ETS1 and ERGB gene products are reduced. These results demonstrate that the regulation of ets family of genes is complex and depends on cell type. This observation leads to the conclusion that the regulation of ets target genes, will be dependent, in part, upon the type of ets genes expressed in each particular cell type.

Expression of ets family of genes in systemic lupus erythematosus and Sjogren's syndrome.

We have examined the expression of three members of the ets family of genes, ETS1, ETS2 and ERGB/Fli-1, in lymphocytes from patients with systemic lupus erythematosus and in two murine autoimmune model systems. The ERGB/Fli-1 gene is expressed at a higher level in lymphocytes from autoimmune disease patients than healthy individuals. In addition, we found that the ERGB/Fli-1 gene expression is higher in splenic T-cells from lupus prone mice and in infiltrating lymphocytes in the salivary glands of HTLV-I tax transgenic mice. Taken together, these results suggest that the elevated expression of the ERGB/Fli-1 gene in lymphocytes may be a prelude to the development of autoimmune diseases.

Bronchiectasis in systemic sclerosis. A study using high resolution computed tomography.

OBJECTIVE: To detect noninvasively the presence of bronchiectasis in patients with systemic sclerosis (SSc), through the use of high resolution chest computed tomography (HRCT). METHODS: Twenty two patients with SSc, of whom 13 with diffuse and 9 with limited disease, besides a complete history, physical and routine laboratory and immunologic profile, were evaluated by pulmonary function testing and HRCT. The chi square test with Yates' correction, the Fisher's exact test, the Fisher's test (F test) and the "t" test were used for statistical analysis of the results. RESULTS: Eleven patients (50.0%) had decreased carbon monoxide diffusing lung capacity (DLCO) and, out of these, four had restrictive lung disease, based on a combined decrease of forced vital capacity (FVC) and total lung capacity (TLC). Another two patients exhibited this pattern without DLCO impairment. HRCT revealed a ground glass picture in 15 patients (68.2%), fibrosis in 9 (40.9%) (of which 5 with ground glass as well), and cylindrical bronchiectasis in 13 (59.1%). Bronchiectasis was more common in diffuse than in limited SSc, and the difference approached but did not reach the level of statistical significance. On the other hand, it was not correlated with either decreased DLCO, presence of ground glass and fibrosis, or with patients' age and disease duration. CONCLUSION: Although the number of patients included in our study is relatively small, our data, for the first time in the literature, indicate a significant association between scleroderma and bronchiectasis. Bronchiectasis should be included in the list of pulmonary manifestations of SSc, and SSc in the list of conditions causing bronchiectasis.

Asymptomatic gastrocnemius muscle biopsy: an extremely sensitive and specific test in the pathologic confirmation of sarcoidosis presenting with hilar adenopathy.

OBJECTIVE: To evaluate asymptomatic gastrocnemius muscle biopsy as a tool in the histologic confirmation of the diagnosis of sarcoidosis. METHODS: Twenty-two patients admitted over a 2-year period to our department with bilateral hilar adenopathy and a variety of symptoms compatible with sarcoidosis were studied prospectively. Besides a complete history and physical, serum angiotensin converting enzyme (SACE) determination, pulmonary function, slit lamp eye examination, PPD skin test, gallium 67 scan and gastrocnemius muscle biopsy were performed. RESULTS: The biopsy revealed non-caseating granuloma in all patients, confirming the diagnosis of sarcoidosis. No other patient in our department received this diagnosis over the 2-year period of the study. The procedure was well tolerated by all patients and almost zero morbidity was noted. Erythema nodosum was present in 68.2% of the patients, PPD was negative in all of them, SACE was elevated in 59.1% and pulmonary function was normal in the majority. CONCLUSION: The impressive sensitivity of asymptomatic gastrocnemius muscle biopsy, its safety and ease of performance, along with the extreme rarity of muscle involvement by other granulomatous diseases included in the differential diagnosis, may render it the procedure of choice for the histologic confirmation of sarcoidosis presenting with hilar adenopathy.