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.

Long-term outcomes of laparoscopic large hiatus hernia repair with nonabsorbable mesh.

The use of mesh to augment suture repair of large hiatus hernias remains controversial. Repair with mesh may help reduce the recurrence rate of primary repair, but concerns about the potential for serious complications, such as mesh erosion or stricturing, continue to limit its use. We aim to evaluate the long-term outcome of primary hiatus hernia repair with lightweight polypropylene mesh (TiMesh) specifically looking at rates of clinical recurrence, dysphagia, and mesh-related complications. From a prospectively maintained database, 50 consecutive patients who underwent elective primary laparoscopic hiatal hernia repair with TiMesh between January 2005 and December 2007 were identified. Case notes and postoperative endoscopy reports were reviewed. Clinical outcomes were evaluated using a structured questionnaire, including a validated dysphagia score. Of the 50 patients identified, 36 (72%) were contactable for follow-up. At a median follow-up of 9 years, the majority of patients (97%) regarded their surgery as successful. Twelve patients (33%) reported a recurrence of their symptoms, but only 4 (11%) reported that their symptoms were as severe as prior to the surgery. There was no significant difference between pre- and postoperative dysphagia scores. Postoperative endoscopy reports were available for 32 patients at a median time point of 4 years postoperatively, none of which revealed any mesh-related complications. One patient had undergone a revision procedure for a recurrent hernia at another institution. In this series, primary repair of large hiatus hernia with nonabsorbable mesh was not associated with any adverse effects over time. Patient satisfaction with symptomatic outcome remained high in the long term.

The past, present and future of polymicrobial infection research: Modelling, eavesdropping, terraforming and other stories.

Over the last two centuries, great advances have been made in microbiology as a discipline. Much of this progress has come about as a consequence of studying the growth and physiology of individual microbial species in well-defined laboratory media; so-called "axenic growth". However, in the real world, microbes rarely live in such "splendid isolation" (to paraphrase Foster) and more often-than-not, share the niche with a plethora of co-habitants. The resulting interactions between species (and even between kingdoms) are only very poorly understood, both on a theoretical and experimental level. Nevertheless, the last few years have seen significant progress, and in this review, we assess the importance of polymicrobial infections, and show how improved experimental traction is advancing our understanding of these. A particular focus is on developments that are allowing us to capture the key features of polymicrobial infection scenarios, especially as those associated with the human airways (both healthy and diseased).

Use of radiological information system data in Clinical Portal database to screen for missed abdominal aortic aneurysms.

INTRODUCTION: New Zealand lacks a formal abdominal aortic aneurysm screening programme and owing to its rural nature, many patients have limited access to vascular surgery. Patients with vascular emergencies often have limited treatment options locally, especially if they present perimortem. In our small hospital in Whanganui, with the nearest vascular centre more than 150km away, there are cases of aneurysms diagnosed incidentally on radiology reporting but lost to follow-up. METHODS: Clinical Portal (CP) is a widely used patient-centred dashboard for viewing health information that is managed by Orion Health. A search strategy utilising the CP common database was devised that aimed to find aneurysms which were not followed up. This search was performed retrospectively for all imaging within a 5-month period. RESULTS: Some 294 scans were flagged and 53 patients with aneurysms were found. Of these patients, 36 had follow-up by the ordering provider and 17 (32%) were found to have been lost to follow-up. CONCLUSIONS: Our pilot study demonstrated high rates of loss to follow-up and a lack of communication of important health information across multiple health disciplines in the region, and represents a potential method for identifying 'lost' aneurysms. For patients in rural communities, this may be critical to preventing future complications from aneurysmal disease.

A luminous fast radio burst that probes the Universe at redshift 1.

Fast radio bursts (FRBs) are millisecond-duration pulses of radio emission originating from extragalactic distances. Radio dispersion is imparted on each burst by intervening plasma, mostly located in the intergalactic medium. In this work, we observe the burst FRB 20220610A and localize it to a morphologically complex host galaxy system at redshift 1.016 ± 0.002. The burst redshift and dispersion measure are consistent with passage through a substantial column of plasma in the intergalactic medium and extend the relationship between those quantities measured at lower redshift. The burst shows evidence for passage through additional turbulent magnetized plasma, potentially associated with the host galaxy. We use the burst energy of 2 × 1042 erg to revise the empirical maximum energy of an FRB.

Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

PURPOSE: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS: We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS: Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS: We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

General paediatric surgery for patients aged under 5 years: a 5-year experience at a district general hospital.

Introduction The gradual shift of general paediatric surgery (GPS) provision from district general hospitals (DGH) to specialised units is well recognised in the UK. The consequences of centralisation include a reduction in exposure to GPS for current surgical trainees. The GPS practice of a DGH is examined here. Methods All operations performed on children aged under 5 years over a 5-year period were identified using the local electronic operation database. Electronic hospital records and clinic letters were accessed to collect data on demographics, operations performed and outcome measures. Results 472 GPS operations were performed on children between the age of 22 days and 5 years between 2009 and 2014, of which 43 were on an emergency basis and 105 were performed on patients aged less than 1 year. Three patients were admitted following day case surgery. Six patients were readmitted within 30 days. Complication rates for all procedures and the four most common procedures were similar to those found in published literature. Conclusions GPS for patients aged less than 5 years is comparatively safe in the DGH setting. The training opportunities available at DGHs are invaluable to surgical trainees and vital for sustaining the future provision of GPS by such hospitals.

Differentiating sepsis from non-infectious systemic inflammation based on microvesicle-bacteria aggregation.

Sepsis is a severe medical condition and a leading cause of hospital mortality. Prompt diagnosis and early treatment has a significant, positive impact on patient outcome. However, sepsis is not always easy to diagnose, especially in critically ill patients. Here, we present a conceptionally new approach for the rapid diagnostic differentiation of sepsis from non-septic intensive care unit patients. Using advanced microscopy and spectroscopy techniques, we measure infection-specific changes in the activity of nano-sized cell-derived microvesicles to bind bacteria. We report on the use of a point-of-care-compatible microfluidic chip to measure microvesicle-bacteria aggregation and demonstrate rapid (≤1.5 hour) and reliable diagnostic differentiation of bacterial infection from non-infectious inflammation in a double-blind pilot study. Our study demonstrates the potential of microvesicle activities for sepsis diagnosis and introduces microvesicle-bacteria aggregation as a potentially useful parameter for making early clinical management decisions.

Psychopathology in epilepsy: how great is the risk?

The relationship between epilepsy and psychiatric disorder in general and the relationship between epilepsy and psychosis in particular remain controversial issues of long standing. In order to reexamine these central issues concerned with epilepsy/psychopathology relationships, we utilized a Minnesota Multiphasic Personality Inventory (MMPI) sequential diagnostic system to reanalyze 87 published MMPI profiles of patients with epilepsy, other neurological disorders, and chronic physical illnesses encompassing a total of 2786 patients. We found that overall rates of psychopathology were not increased in epilepsy. However, when psychopathology was present, the level of psychosis was greatest in patients with epilepsy. The results are related to the larger literature concerned with the relationship between epilepsy and psychopathology.

Neoplastic hypercalcemia: physiologic response to intravenous etidronate disodium.

Following a four-day control period during which an elevated serum calcium level either stabilized or continued to rise despite maximally tolerated saline diuresis, 12 patients with neoplastic hypercalcemia were treated with intravenous etidronate disodium (etidronate) 7.5 mg/kg/day for up to seven days. Serum calcium reverted to normal levels in all patients, with the mean pretreatment serum calcium level of 12.5 +/- 0.4 mg/dl dropping to 9.2 +/- 0.2 mg/dl (p less than 0.01) by Day 7. Elevated urinary calcium (1,107 +/- 134 mg/g creatinine) and hydroxyproline levels (154 +/- 16 mg/g creatinine) declined to 245 +/- 52 mg/g creatinine and 75 +/- 14 mg/g creatinine, respectively, suggesting a marked reduction in bone resorption following treatment. Serum phosphorus levels were unchanged, but urinary phosphorus levels dropped rapidly from 1,181 +/- 125 mg/g creatinine before treatment to 723 +/- 94 mg/g creatinine after two days. Serum parathyroid hormone levels (mid-molecule assay) were suppressed before treatment (64 +/- 16 pg/ml), but rose rapidly to 223 +/- 68 pg/ml by Day 7 of treatment. The value of serum 1,25-dihydroxyvitamin D was initially below normal (16 +/- 3 pg/ml), but rose rapidly with treatment to 42 +/- 12 pg/ml by Day 7. Symptoms of hypercalcemia and bone pain improved with treatment, and no serious adverse reactions to treatment were encountered. Intravenous etidronate is apparently an effective and safe treatment for neoplastic hypercalcemia.

Image-guided central venous catheters for apheresis.

Apheresis is an increasingly important procedure in the treatment of a variety of conditions, sometimes performed via peripheral access because of concern over major complications associated with central venous catheter (CVC) placement. This study sought to determine the safety and success for ultrasound and fluoroscopically guided, non-tunneled dual lumen CVCs placed for apheresis. Prospective data collection was made of 200 attempted CVC placements in the radiology department utilizing real time sonographic guidance. The complications relating to placement were noted in all and the number of passes required for venepuncture and whether a single wall puncture was achieved was recorded in 185 cases. Duration of catheterization and reason for line removal were recorded in all. Our study group included 71 donors providing peripheral blood stem cells for allogeneic transplant. CVCs were successfully placed in all patients, 191 lines in the internal jugular and seven in the femoral vein. 86.5% required only a single pass and 80.5% with only anterior wall puncture. Inadvertent but clinically insignificant arterial puncture occurred in six (3%) cases. In no case did this prevent line placement. There were no other procedure-related complications. 173 (87.4%) catheters were removed the same day. No catheters were removed prematurely. There was one case of prolonged venous bleeding. Our study demonstrates the safety of central venous catheters for apheresis provided that duration of catheterization is short and real-time sonographic guidance is used for the puncture, and guide wire and catheter placement are confirmed fluoroscopically.

A randomized prospective study of early follicular or midluteal initiation of long protocol gonadotropin-releasing hormone in an in vitro fertilization program.

OBJECTIVE: To determine the optimum menstrual cycle time to initiate a long-protocol gonadotropin-releasing hormone agonist (GnRH-a) down-regulation regimen before hMG stimulation before IVF. DESIGN: Randomized, prospective, single, first cycle study. SETTING: University teaching hospital. PATIENTS: Eighty-six infertile couples undergoing IVF-ET attempt under rules for Ireland. INTERVENTION: Gonadotropin-releasing hormone agonist administered intranasally from day 1 or 21 of menstrual cycle. Human menopausal gonadotropin commenced when pituitary down-regulation was confirmed. MAIN OUTCOME MEASURES: Ovarian response, cancellation, fertilization, and pregnancy rates. RESULTS: No significant differences found between day 1 and day 21 initiation. But starting on day 1 is more easily recognizable by patients and avoids the possibility of administering GnRH-a in the presence of an unsuspected pregnancy. CONCLUSIONS: Both follicular and luteal phase initiation of GnRH-a long-protocol down-regulation are equally efficacious. In our clinical context, patients and management favor commencing on day 1.

A randomized prospective assessor-blind evaluation of luteinizing hormone dosage and in vitro fertilization outcome.

OBJECTIVE: To determine the effect of exogenous LH dosage on IVF outcome. DESIGN: Single-blinded (assessor-blinded) study with random assignment of treatment groups. SETTING: Human Assisted Reproduction Unit, Rotunda Hospital, Dublin, Ireland. PATIENT(S): Infertile normogonadotropic women undergoing their first cycle of IVF were studied. INTERVENTION(S): Patients were randomized to gonadotropin drugs with varying doses of LH per ampule: recombinant FSH containing no LH (group 0, n = 39), urinary FSH containing <1 IU of LH per ampule (group 1, n = 30), hMG containing 25 IU of LH per ampule (group 25, n = 30), and hMG containing 75 IU of LH per ampule (group 75, n = 29). The FSH dose was kept constant at 75 IU per ampule. A long-protocol GnRH-analog regimen was used. MAIN OUTCOME MEASURE(S): Dose and duration of gonadotropin stimulation, follicle and oocyte numbers, implantation rate, and pregnancy rate. RESULT(S): The median duration of ovarian stimulation; median number of gonadotropin ampules used; serum E2 levels; and numbers of follicles, oocytes, and embryos were similar among the four groups. Median LH levels on the day of hCG administration, however, differed significantly. Live birth rates per cycle differed markedly, but statistical significance was not achieved (23%, 7%, 20%, and 31% for groups 0, 1, 25, and 75, respectively). A significant trend in implantation rates was noted with increasing LH dosage of the urinary preparations (19%, 10%, 18%, and 28% for groups 0, 1, 25, and 75, respectively). CONCLUSION(S): In the present study, although the residual endogenous LH after down-regulation was adequate for ovarian response and E2 synthesis, the addition of exogenous LH improved implantation. An FSH/LH ratio of 75/75 IU per ampule appeared to be the optimum dose.

Acute exacerbation of vasculitis during interferon-alpha therapy for hepatitis C-associated cryoglobulinaemia.

A significant, previously unreported, adverse reaction to interferon-alpha therapy is reported. Immediately after the commencement of low dose therapy a man with hepatitis-C associated cryoglobulinaemia developed a purpuric rash and a severe, reversible impairment of renal function. This observation may elucidate the immunopathogenesis of vasculitis.

Radioimmunoassay and enzymeimmunoassay of plasma progesterone as monitors of progesterone sponge treatment in ewes.

The daily plasma progesterone (P) concentrations achieved during insertion of P (750 mg) sponges into two groups of ewes were examined. Group I received prostaglandin (PG) treatment, which was required to suppress the P production (to levels of < 0.3 ng hormone/ml plasma) from the corpora lutea (CL) of a previous superovulation treatment, following which these Group I ewes and the anestrous Group II ewes were sponge treated. Radioimmunoassay (RIA) and enzymeimmunoassay (EIA) were used to measure the P levels in both groups. Progesterone (750 mg) sponges with and without citric acid impregnation were inserted into all the ewes for 12 days (d). Citric acid lowered the P levels reaching the plasma from the sponges, but it did not mask the characteristic profile (during the treatments) determined by the states of the ewes (single PG and double PG injected, Group I or in the anestrous Group II). The plasma P levels in Group I and II ewes rose to at least 7.0 ng/ml at intervals during treatment. The duration and magnitude of the P concentrations in the plasma were higher in the single PG compared with the double PG ewes during sponge insertion in Group I. The anestrous Group II ewes showed two major peaks (Day 1, P<0.01 and Days 11 to 12, P<0.05) during sponge treatment. A P level > 2.0 ng/ml was maintained over the entire treatment in the single PG and in the anestrous hormone-treated ewes, and was of shorter duration (7 d) in the double PG-treated animals. These endogenous patterns in P profiles of the ewes indicate that the hormone level during sponge insertion varies in magnitude and duration, parameters determined by the physiological/endocrinological state of the ewes at the start of the treatment. The EIA correlated significantly (P<0.001) with the RIA for the measurement of P concentration, when analyzed daily on an individual animal basis.

Duplex-guided compression of femoral artery false aneurysms reduces the need for surgery.

In a 1-year period, 13 patients underwent duplex-guided compression (DGC) of femoral artery false aneurysms. Of the 13 false aneurysms, 11 arose after cardiac catheterisation, and DGC was successful in 10 (77%) cases. The number of percutaneous cardiological procedures has risen over the past 5 years, and with time a greater proportion of these procedures have become more complex, involving coronary angioplasty or coronary stenting. The rate of vascular complications has risen from 0.2% in 1991-1992 to 0.61% in 1994-1995. Duplex-guided compression has reduced the number of operations performed for the vascular complications of percutaneous cardiological procedures by 50%. No complications have arisen from DGC, and it is recommended as the first line of management for femoral artery false aneurysms after percutaneous cardiological procedures.

Establishing an intracytoplasmic sperm injection (ICSI) programme for the treatment of male factor infertility in Ireland.

This paper chronicles the introduction and initial experiences of Intra Cytoplasmic Sperm Injection (ICSI) as a treatment for severe male factor infertility in Ireland. Following initial development of the technique using a bovine model, therapy was offered clinically from September 1995. Up to March 1996 a total of 60 couples underwent the procedure. Fertilisation and embryo transfers were achieved in 50 of these (83.3 percent). Fourteen (23 percent) became clinically pregnant per cycle commenced, 28 percent per embryo transfer. Despite a drop in the total number of oocytes available, fertilisation rates rose over the 6 months of the study from 22 percent to 54 percent. There were 2 miscarriages (14.2 percent) and the multiple pregnancy rate was 28.5 percent. Eight singletons, 2 twins and 2 triplet sets have been successfully delivered. Provided there is proper patient selection, ICSI should prove a valuable addition to treatment options available to infertile couples in Ireland.

Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort.

INTRODUCTION: Faecal peritonitis (FP) is a common cause of sepsis and admission to the intensive care unit (ICU). The Genetics of Sepsis and Septic Shock in Europe (GenOSept) project is investigating the influence of genetic variation on the host response and outcomes in a large cohort of patients with sepsis admitted to ICUs across Europe. Here we report an epidemiological survey of the subset of patients with FP. OBJECTIVES: To define the clinical characteristics, outcomes and risk factors for mortality in patients with FP admitted to ICUs across Europe. METHODS: Data was extracted from electronic case report forms. Phenotypic data was recorded using a detailed, quality-assured clinical database. The primary outcome measure was 6-month mortality. Patients were followed for 6 months. Kaplan-Meier analysis was used to determine mortality rates. Cox proportional hazards regression analysis was employed to identify independent risk factors for mortality. RESULTS: Data for 977 FP patients admitted to 102 centres across 16 countries between 29 September 2005 and 5 January 2011 was extracted. The median age was 69.2 years (IQR 58.3-77.1), with a male preponderance (54.3%). The most common causes of FP were perforated diverticular disease (32.1%) and surgical anastomotic breakdown (31.1%). The ICU mortality rate at 28 days was 19.1%, increasing to 31.6% at 6 months. The cause of FP, pre-existing co-morbidities and time from estimated onset of symptoms to surgery did not impact on survival. The strongest independent risk factors associated with an increased rate of death at 6 months included age, higher APACHE II score, acute renal and cardiovascular dysfunction within 1 week of admission to ICU, hypothermia, lower haematocrit and bradycardia on day 1 of ICU stay. CONCLUSIONS: In this large cohort of patients admitted to European ICUs with FP the 6 month mortality was 31.6%. The most consistent predictors of mortality across all time points were increased age, development of acute renal dysfunction during the first week of admission, lower haematocrit and hypothermia on day 1 of ICU admission.