Description, life cycle, and phylogenetics of Proterometra wigglewomble n. sp. (Digenea: Azygiidae) from the Cahaba River, Alabama, U.S.A.

We herein describe Proterometra wigglewomble n. sp. (Digenea: Azygiidae: Azygiinae) from the Cahaba River, Alabama, USA, which asexually reproduces in the compact elimia, Elimia showalteri (Lea, 1860) (Cerithioidea: Pleuroceridae) and matures in the oesophagus of the blackbanded darter, Percina nigrofasciata (Agassiz, 1854) (Perciformes: Percidae). Adults of the new species differ from congeners by having a small body and eggs having a wholly fimbriated surface that appears as a cilia-like brush border. Live naturally-shed cercariae of the new species differ from those of its congeners by having a strongly claviform tail stem bearing aspinose mammillae, a single furca, excretory pores that open on the posterior margin of the single furca, and few eggs in the cercarial distome. The behaviour of the cercaria further differentiates the new species. Naturally-shed cercariae of P. wigglewomble secrete a jelly-like adhesive that coats the surface of the furca and evidently facilitates attachment to the surface of glass, plastic, and snail shell. Attached cercariae vigorously wiggle and thrash about once attached, as if mimicking the larva of a stream insect so as to lure the blackbanded darter to eat it. Phylogenetic analyses recovered monophyletic Azygiidae, comprising monophyletic Leuceruthrinae Goldberger, 1911 and polyphyletic Azygiinae Lühe, 1909. The present study is the largest taxon sampling for Azygiidae and the first to include 28S sequences of Leuceruthrus. Compact elimia and blackbanded darter are new host records for Proterometra. The new species is the 3rd congener reported from the Cahaba River, a region renowned for its fish and snail endemic biodiversity.

Pilot study of a combined genomic and epidemiologic surveillance program for hospital-acquired multidrug-resistant pathogens across multiple hospital networks in Australia.

OBJECTIVES: To conduct a pilot study implementing combined genomic and epidemiologic surveillance for hospital-acquired multidrug-resistant organisms (MDROs) to predict transmission between patients and to estimate the local burden of MDRO transmission. DESIGN: Pilot prospective multicenter surveillance study. SETTING: The study was conducted in 8 university hospitals (2,800 beds total) in Melbourne, Australia (population 4.8 million), including 4 acute-care, 1 specialist cancer care, and 3 subacute-care hospitals. METHODS: All clinical and screening isolates from hospital inpatients (April 24 to June 18, 2017) were collected for 6 MDROs: vanA VRE, MRSA, ESBL Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp), and carbapenem-resistant Pseudomonas aeruginosa (CRPa) and Acinetobacter baumannii (CRAb). Isolates were analyzed and reported as routine by hospital laboratories, underwent whole-genome sequencing at the central laboratory, and were analyzed using open-source bioinformatic tools. MDRO burden and transmission were assessed using combined genomic and epidemiologic data. RESULTS: In total, 408 isolates were collected from 358 patients; 47.5% were screening isolates. ESBL-Ec was most common (52.5%), then MRSA (21.6%), vanA VRE (15.7%), and ESBL-Kp (7.6%). Most MDROs (88.3%) were isolated from patients with recent healthcare exposure.Combining genomics and epidemiology identified that at least 27.1% of MDROs were likely acquired in a hospital; most of these transmission events would not have been detected without genomics. The highest proportion of transmission occurred with vanA VRE (88.4% of patients). CONCLUSIONS: Genomic and epidemiologic data from multiple institutions can feasibly be combined prospectively, providing substantial insights into the burden and distribution of MDROs, including in-hospital transmission. This analysis enables infection control teams to target interventions more effectively.

Deciphering the Allosteric Binding Mechanism of the Human Tropomyosin Receptor Kinase A ( hTrkA) Inhibitors.

Access to cryptic binding pockets or allosteric sites on a kinase that present themselves when the enzyme is in a specific conformational state offers a paradigm shift in designing the next generation small molecule kinase inhibitors. The current work showcases an extensive and exhaustive array of in vitro biochemical and biophysical tools and techniques deployed along with structural biology efforts of inhibitor-bound kinase complexes to characterize and confirm the cryptic allosteric binding pocket and docking mode of the small molecule actives identified for hTrkA. Specifically, assays were designed and implemented to lock the kinase in a predominantly active or inactive conformation and the effect of the kinase inhibitor probed to understand the hTrkA binding and hTrkB selectivity. The current outcome suggests that inhibitors with a fast association rate take advantage of the inactive protein conformation and lock the kinase state by also exhibiting a slow off-rate. This in turn shifts the inactive/active state protein conformational equilibrium cycle, affecting the subsequent downstream signaling.

Large paraspinal abscess as a complication of infliximab therapy in Crohn's disease.

We report a 36-year-old man who developed a large epidural and paraspinal abscess as a complication of infliximab therapy being used for underlying Crohn's disease. Cultures of the collection grew methicillin-susceptible Staphylococcus aureus, and treatment consisted of abscess drainage, prolonged intravenous and oral flucloxacillin and temporary withholding of his infliximab. While infection-related complications are well described with infliximab therapy, this is the first description of a large paraspinal abscess with epidural extension.

Planning After Stroke Survival: Advance Care Planning in the Stroke Clinic.

Background Stroke survivors have high rates of mortality and recurrent stroke. Stroke patients are often unable to participate in decision making, highlighting the need for advance care planning ( ACP ) in poststroke care. We sought to better understand experiences and perceptions around stroke risk and ACP in our stroke clinic. Methods and Results Clinic patients completed the Planning After Stroke Survival survey assessing (1) advance directive ( AD ) documentation and ACP conversations, (2) factors associated with ADs and ACP , (3) perceptions of stroke risk, and (4) ACP needs. We used a physician survey and the electronic medical record to assess clinical and demographic information. We collected 219 surveys (78% response rate). Forty-five percent reported having completed ADs , although the correlation between patient report and EMS documentation of ADs was low. Most patients (73%) had discussed ACP , and 58% desired additional conversation. Predictors of completing ADs included age (≥65 years; odds ratio, 4.8; 95% CI, 2.3-10.1), white race (odds ratio, 3.1; 95% CI , 1.2-7.8), milder poststroke disability (modified Rankin Scale score ≤1; odds ratio, 2.9; 95% CI , 1.3-6.4), having previously discussed ACP with a physician (odds ratio, 4.8; 95% CI , 2.0-11.7), and discussing risk of stroke recurrence (odds ratio, 2.2; 95% CI , 1.1-4.5). Conclusions Stroke survivors had low AD completion rates and desired more conversations about stroke risk and ACP . Completed ADs were inconsistently documented in the electronic medical record. These findings provide guidance to improve ACP in our stroke clinic and may provide a model for others interested in enhancing ACP and ultimately goal-concordant care.

Herpes simplex virus-2 transmission following solid organ transplantation: Donor-derived infection and transplantation from prior organ recipients.

BACKGROUND: Owing to limited availability of donor organs, previous solid organ transplant (SOT) recipients are increasingly considered as potential organ donors. We report donor-derived transmission of herpes simplex virus type-2 (HSV-2) to two clusters of SOT recipients with transmission from the original donor and an HSV-2-infected recipient who subsequently became a donor. METHODS: We reviewed medical records of the donors and recipients in both clusters. Pre-transplant serology and virological features of HSV-2 were characterized. Genotyping of HSV-2 isolates to determine potential for donor transmission of HSV-2 through transplantation of organs from prior organ recipients was performed. RESULTS: A kidney-pancreas recipient died day 9 post transplant. Following confirmation of brain death, the lungs and recently transplanted kidney were donated to two further recipients. The liver was not retrieved, but biopsy confirmed HSV-2 infection. Testing on the original donor showed negative HSV-2 polymerase chain reaction and HSV immunoglobulin (Ig)M, but positive HSV-2 IgG. The liver recipient from the original donor developed HSV-2 hepatitis and cutaneous infection that responded to treatment with intravenous acyclovir. In the second cluster, lung and kidney recipients both developed HSV-2 viremia that was successfully treated with antiviral therapy. Genotyping of all HSV-2-positive samples showed 100% sequence homology for three recipients. CONCLUSIONS: Donor-derived HSV infection affected two clusters of recipients because of transplantation of organs from a prior organ recipient. HSV should be considered as a possible cause of illness in febrile SOT recipients in the immediate post-transplant period and may cause disseminated disease and re-infection in HSV-2-seropositive recipients. Testing of HSV serology and prophylaxis may be considered in SOT recipients not receiving cytomegalovirus prophylaxis.

Target-Specific Assay for Rapid and Quantitative Detection of Mycobacterium chimaera DNA.

Mycobacterium chimaera is an opportunistic environmental mycobacterium belonging to the Mycobacterium avium-M. intracellulare complex. Although most commonly associated with pulmonary disease, there has been growing awareness of invasive M. chimaera infections following cardiac surgery. Investigations suggest worldwide spread of a specific M. chimaera clone, associated with contaminated hospital heater-cooler units used during the surgery. Given the global dissemination of this clone, its potential to cause invasive disease, and the laboriousness of current culture-based diagnostic methods, there is a pressing need to develop rapid and accurate diagnostic assays specific for M. chimaera Here, we assessed 354 mycobacterial genome sequences and confirmed that M. chimaera is a phylogenetically coherent group. In silico comparisons indicated six DNA regions present only in M. chimaera We targeted one of these regions and developed a TaqMan quantitative PCR (qPCR) assay for M. chimaera with a detection limit of 100 CFU/ml in whole blood spiked with bacteria. In vitro screening against DNA extracted from 40 other mycobacterial species and 22 bacterial species from 21 diverse genera confirmed the in silico-predicted specificity for M. chimaera Screening 33 water samples from heater-cooler units with this assay highlighted the increased sensitivity of PCR compared to culture, with 15 of 23 culture-negative samples positive by M. chimaera qPCR. We have thus developed a robust molecular assay that can be readily and rapidly deployed to screen clinical and environmental specimens for M. chimaera.

Epidemiology and management of Buruli ulcer.

Buruli ulcer (Mycobacterium ulcerans infection) is a neglected tropical disease of skin and subcutaneous tissue that can result in long-term cosmetic and functional disability. It is a geographically restricted infection but transmission has been reported in endemic areas in more than 30 countries worldwide. The heaviest burden of disease lies in West and Sub-Saharan Africa where it affects children and adults in subsistence agricultural communities. Mycobacterium ulcerans infection is probably acquired via inoculation of the skin either directly from the environment or indirectly via insect bites. The environmental reservoir and exact route of transmission are not completely understood. It may be that the mode of acquisition varies in different parts of the world. Because of this uncertainty it has been nicknamed the 'mysterious disease'. The therapeutic approach has evolved in the past decade from aggressive surgical resection alone, to a greater focus on antibiotic therapy combined with adjunctive surgery.

Treatment and prevention of Mycobacterium ulcerans infection (Buruli ulcer) in Australia: guideline update.

• Guidelines reflecting contemporary clinical practice in the management of Buruli ulcer (Mycobacterium ulcerans infection) in Australia were published in 2007. • Management has continued to evolve, as new evidence has become available from randomised trials, case series and increasing clinical experience with oral antibiotic therapy. • Therefore, guidelines on the diagnosis, treatment and prevention of Buruli ulcer in Australia have been updated. They include guidance on the new role of antibiotics as first-line therapy; the shortened duration of antibiotic treatment and the use of all-oral antibiotic regimens; the continued importance, timing and role of surgery; the recognition and management of paradoxical reactions during antibiotic treatment; and updates on the prevention of disease.

The fish tank strikes again: metachronous nontuberculous mycobacterial skin infection in an immunosuppressed host.

An 82-year-old woman on long-term prednisolone for chronic obstructive airways disease presented with a 2-month history of nodules on her left forearm. This occurred 10 years after nodules on her right forearm caused by a culture-proven Mycobacterium marinum infection. Histopathological examination, polymerase chain reaction and culture of biopsy specimens were positive for M. chelonae. To our knowledge this is the first case of metachronous nontuberculous mycobacterial skin infection reported, and it highlights the diagnostic and therapeutic challenges of such infections.

Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases.

Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.

Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia.

We describe laboratory-confirmed influenza A pandemic (H1N1) 2009 in 17 hospitalized recipients of a hematopoietic stem cell transplant (HSCT) (8 allogeneic) and in 15 patients with malignancy treated at 6 Australian tertiary centers during winter 2009. Ten (31.3%) patients were admitted to intensive care, and 9 of them were HSCT recipients. All recipients of allogeneic HSCT with infection <100 days posttransplantation or severe graft-versus-host disease were admitted to an intensive care unit. In-hospital mortality rate was 21.9% (7/32). The H275Y neuraminidase mutation, which confers oseltamivir resistance developed in 4 of 7 patients with PCR positive for influenza after > or = 4 days of oseltamivir therapy. Three of these 4 patients were critically ill. Oseltamivir resistance in 4 (13.3%) of 30 patients who were administered oseltamivir highlights the need for ongoing surveillance of such resistance and further research on optimal antiviral therapy in the immunocompromised.

Successful treatment of Mycobacterium ulcerans osteomyelitis with minor surgical debridement and prolonged rifampicin and ciprofloxacin therapy: a case report.

INTRODUCTION: Treatment for osteomyelitis-complicating Mycobacterium ulcerans infection typically requires extensive surgery and even amputation, with no reported benefit from adjunctive antibiotics. CASE PRESENTATION: We report a case of an 87-year-old woman with M. ulcerans osteomyelitis that resolved following limited surgical debridement and 6 months of therapy with rifampicin and ciprofloxacin. CONCLUSION: M. ulcerans osteomyelitis can be successfully treated with limited surgical debridement and adjunctive oral antibiotics.

Outcomes for Mycobacterium ulcerans infection with combined surgery and antibiotic therapy: findings from a south-eastern Australian case series.

OBJECTIVE: To describe the effect of antibiotics on outcomes of treatment for Buruli or Bairnsdale ulcer (BU) in patients on the Bellarine Peninsula in south-eastern Australia. DESIGN: Observational, non-randomised study with data collected prospectively or through medical record review. PATIENTS AND SETTING: All 40 patients with BU managed by staff of Barwon Health's Geelong Hospital (a public, secondary-level hospital) between 1 January 1998 and 31 December 2004. MAIN OUTCOME MEASURES: Epidemiology, clinical presentation, diagnosis, treatment and clinical outcomes. RESULTS: There were 59 treatment episodes; 29 involved surgery alone, 26 surgery plus antibiotics, and four antibiotics alone. Of 55 episodes where surgery was performed, minor surgery was required in 22, and major surgery in 33. Failure rates were 28% for surgery alone, and 19% for surgery plus antibiotics. Adjunctive antibiotic therapy was associated with increased treatment success for lesions with positive histological margins (P < 0.01), and lesions requiring major surgery for treatment of a first episode (P < 0.01). The combination of rifampicin and ciprofloxacin resulted in treatment success in eight of eight episodes, and no patients ceased therapy because of side effects with this regimen. CONCLUSIONS: Adjunctive antibiotic therapy may increase the effectiveness of BU surgical treatment, and this should be further assessed by larger randomised controlled trials. The combination of rifampicin and ciprofloxacin appears the most promising.

Consensus recommendations for the diagnosis, treatment and control of Mycobacterium ulcerans infection (Bairnsdale or Buruli ulcer) in Victoria, Australia.

Mycobacterium ulcerans causes slowly progressive, destructive skin and soft tissue infections, known as Bairnsdale or Buruli ulcer (BU). Forty-six delegates with experience in the management of BU attended a 1-day conference in Melbourne on 10 February 2006, with the aim of developing a consensus approach to the diagnosis, treatment and control of BU. An initial draft document was extended and improved during a facilitated round table discussion. BU is an environmental infection that occurs in specific locations. The main risk factor for infection is contact with an endemic area. Prompt cleaning of abrasions sustained outdoors, wearing protective clothing, and avoiding mosquito bites may reduce an individual's risk of infection. BU can be rapidly and accurately diagnosed by polymerase chain reaction testing of ulcer swabs or biopsies. Best outcomes are obtained when the diagnosis is made early. To aid early diagnosis, health authorities should keep local populations informed of new outbreaks. BU is best treated with surgical excision, which, if possible, should include a small rim of healthy tissue. For small lesions this may be all that is required. However, there is a role for antibiotics for more extensive disease, and their use may allow more conservative surgery.

Should medical students be routinely offered BCG vaccination?

BCG vaccination is no longer routinely offered to all medical students in Victoria. Practices in Australia's 15 medical schools vary widely with respect to BCG vaccination and surveillance for tuberculosis (TB) infection during the medical course. Health care workers can be exposed to TB in Australian hospitals, but the risk is much higher if they undertake work in countries with a high prevalence of TB, such as during student electives. BCG vaccination is safe, cheap and protects 50% or more of recipients from active TB, including multidrug-resistant TB. Protection is long-lasting, requires only a single dose, and there is new evidence that BCG may prevent primary infections, not just active disease. Although BCG vaccination interferes with the interpretation of the tuberculin skin test (TST), newer tests (QuantiFERON-TB Gold, T-SPOT.TB) are unaffected by BCG vaccination. We propose a standard approach for all Australian medical students that includes screening with TST and QuantiFERON-TB Gold/T-SPOT.TB at course entry, and recommending BCG vaccination for students who test negative, provided they have not previously received BCG vaccine.

Transferability of six pesticides from agricultural sprayer surfaces.

Secondary exposure to pesticide residues on the external surfaces of sprayers does not currently form part of the risk assessment process. A measure of the ease with which residues may be transferred from the sprayer surface to the operator would enhance the accuracy of any such assessment. This study quantified the dislodgeability of six pesticides from sprayer surfaces in order to calculate the transfer efficiencies. The transfer efficiency was compound dependent, ranging from 80% for azoxystrobin to <25% for flusilazole and tebuconazole. When the washed and unwashed surfaces were analysed separately, more pendimethalin and isoproturon residues were removed from the wet surface compared with the dry surface. The variation in results for the different compounds highlights the need to consider a range of compounds to form generic statements to support guidelines regarding operator exposure to pesticide residues on sprayers.