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BackgroundSuccessful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). A clinically meaningful and simple biomarker of immunosuppression could potentially assist clinicians in their decision-making. We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients.MethodsA prospective observational multicenter study of 73 adult allogeneic HSCT recipients was conducted in Melbourne, Australia. Eligible participants were >18 years and at risk of cytomegalovirus disease. T-cell responses to PHA were assessed at 3, 6, 9, and 12 months post-HSCT using the commercial quantiferon-cytomegalovirus assay, which quantifies IFN-γ production by ELISA following stimulation with PHA. A low response was defined as IFN-γ

Cardio-oncology is a multidisciplinary field focusing on the management and prevention of cardiovascular complications in cancer patients and survivors. While the initial focus of this specialty was on heart failure associated with anthracycline use, novel anticancer agents are increasingly utilized and are associated with many other cardiotoxicities including hypertension, arrhythmias and vascular disease. Since its inception, the field has developed at a rapid pace with the establishment of programs at many major academic institutions and community practices. Given the complexities of this patient population, it is important for providers to possess knowledge of not only cardiovascular disease but also cancer subtypes and their specific therapeutics. Developing a cardio- oncology program at a stand-alone cancer center can present unique opportunities and challenges when compared to those affiliated with other institutions including resource allocation, cardiovascular testing availability and provider education. In this review, we present our experiences establishing the cardio-oncology program at Moffitt Cancer Center and provide guidance to those individuals interested in developing a program at a similar independent cancer institution.

BACKGROUND:Strongyloides seroprevalence is hyper-endemic in many Australian Aboriginal and Torres Strait Islander communities, ranging from 35-60%. We report the impact on Strongyloides seroprevalence after two oral ivermectin mass drug administrations (MDAs) delivered 12 months apart in a remote Australian Aboriginal community. METHODS:Utilizing a before and after study design, we measured Strongyloides seroprevalence through population census with sequential MDAs at baseline and month 12. Surveys at months 6 and 18 determined changes in serostatus. Serodiagnosis was undertaken by ELISA that used sonicated Strongyloides ratti antigen to detect anti-Strongyloides IgG. Non-pregnant participants weighing ≥15 kg were administered a single 200 μg/kg ivermectin dose, repeated after 10-42 days if Strongyloides and/or scabies was diagnosed; others followed a standard alternative algorithm. A questionnaire on clinical symptoms was administered to identify adverse events from treatment and self-reported symptoms associated with serostatus. FINDINGS:We surveyed 1013 participants at the baseline population census and 1060 (n = 700 from baseline cohort and 360 new entrants) at month 12. Strongyloides seroprevalence fell from 21% (175/818) at baseline to 5% at month 6. For participants from the baseline cohort this reduction was sustained at month 12 (34/618, 6%), falling to 2% at month 18 after the second MDA. For new entrants to the cohort at month 12, seroprevalence reduced from 25% (75/297) to 7% at month 18. Strongyloides positive seroconversions for the baseline cohort six months after each MDA were 2.5% (4/157) at month 6 and 1% at month 18, whilst failure to serorevert remained unchanged at 18%. At 12 months, eosinophilia was identified in 59% of baseline seropositive participants and 89% of seropositive new entrants, compared with 47%baseline seronegative participants and 51% seronegative new entrants. Seropositivity was not correlated with haemoglobin or any self-reported clinical symptoms. Clinical symptoms ascertained on the day of treatment and 24-72 hrs after, did not identify any adverse events. SIGNIFICANCE:Two community ivermectin MDAs delivered 12 months apart by trained Aboriginal researchers in collaboration with non-Indigenous researchers resulted in a sustained and significant reduction in Strongyloides seroprevalence over 18 months. Similar reductions were seen in the baseline cohort and new entrants.

In ST-elevation myocardial infarction (STEMI), acute kidney injury (AKI) may increase subsequent morbidity and mortality. Still, it remains difficult to predict AKI risk in these patients. We sought to 1) determine the frequency and clinical outcomes of AKI and, 2) develop, validate and compare a web-based tool for predicting AKI.In a racially diverse series of 1144 consecutive STEMI patients, Stage 1 or greater AKI occurred in 12.9% and was severe (Stage 2-3) in 2.9%. AKI was associated with increased mortality (5.7-fold, unadjusted) and hospital stay (2.5-fold). AKI was associated with systolic dysfunction, increased left ventricular end-diastolic pressures, hypotension and intra-aortic balloon counterpulsation. A computational algorithm (UT-AKI) was derived and internally validated. It showed higher sensitivity and improved overall prediction for AKI (area under the curve 0.76) vs. other published indices. Higher UT-AKI scores were associated with more severe AKI, longer hospital stay and greater hospital mortality.In a large, racially diverse cohort of STEMI patients, Stage 1 or greater AKI was relatively common and was associated with significant morbidity and mortality. A web-accessible, internally validated tool was developed with improved overall value for predicting AKI. By identifying patients at increased risk, this tool may help physicians tailor post-procedural diagnostic and therapeutic strategies after STEMI to reduce AKI and its associated morbidity and mortality.

Purpose: To characterize the onset and type of neovascular events in eyes with central retinal vein occlusion (CRVO) undergoing serial anti-VEGF therapy. Methods: Consecutive eyes undergoing serial intravitreal bevacizumab or ranibizumab injections for treatment of CME secondary to CRVO were identified. Pertinent data was retrospectively collected and included type and onset of the neovascular event, and the treatment free interval from last injection until the neovascular event. Kaplan-Meier life table analysis was performed to determine the differential effects of baseline perfusion status, early initiation of anti-VEGF treatment (within 3 months of CRVO onset) versus later treatment, and continuous (1-month±2 weeks) versus discontinuous treatment interval (>1.5 months) on time until neovascular event. Results: Of 31 eligible eyes, 12 (39%) and 19 (61%) presented with perfused and ischemic CRVO, respectively. The mean duration from CRVO until the onset of any neovascular event was 17.0±10.3 months. The mean treatment-free interval prior to any neovascular event was 6.2±7.3 months. On average, 5.3±3.2 anti-VEGF injections were given prior to any neovascular event. Neovascularization of the iris or angle occurred in 18 eyes (58%), vitreous hemorrhage associated with neovascularization was observed in 9 eyes (29%) and neovascularization of the disc developed in 5 eyes (16%). Neovascular events showed a trend towards occurring later in eyes with perfused CRVO at baseline (log rank test, P=0.07). Conclusion: Neovascular events occur in eyes with CRVO undergoing serial anti-VEGF therapy, and these events may be delayed compared to the natural history of CRVO-associated neovascularization. Iris neovascularization occurred most frequently.

This paper explores the understandings of antibiotics and antimicrobial resistance (AMR) among ethnically diverse informants in Melbourne, Australia. A total of 31 face-to-face semi-structured qualitative interviews were conducted with a sample of ethnic in-patients who were admitted with an acquired antimicrobial infection in a public hospital (n = 7); five hospital interpreters; and ethnic members of the general community (n = 19) as part of a broader study of lay understandings of AMR. Thematic analysis revealed there was poor understanding of AMR, even among informants being treated for AMR infections. Causes of the increasing incidence of AMR were attributed to: weather fluctuations and climate change; a lack of environmental cleanliness; and the arrival of new migrant groups. Asian informants emphasized the need for humoral balance. Antibiotics were viewed as ‘strong’ medicines that could potentially disrupt this balance and weaken the body. Travel back to countries of origin sometimes involved the use of medical services and informants noted that some community members imported antibiotics from overseas. Most used the internet and social media to source health information. There is a lack of information in their own languages. More attention needs to be given to migrant communities who are vulnerable to the development, transmission and infection with resistant bacteria to inform future interventions.

Lyme disease, caused by Borrelia burgdorferi (Bb), can progress to Lyme arthritis (LA). While most patients with LA respond successfully to antibiotic therapy, a small percentage fail to improve, a condition known as antibiotic-refractory Lyme arthritis (ARLA). While T cell responses are known to drive ARLA, molecular mechanisms for ARLA remain unknown. In this issue of the JCI, Dirks et al. isolated disease-specific Th cells from patients with ARLA residing in Germany. A distinct TCR-[beta] motif distinguished ARLA from other rheumatic diseases. Notably, the TCR-[beta] motif was linked predominantly to HLA-DRB1*11 or 13 alleles, which differed from alleles in patients from North America. It also mapped primarily to T peripheral helper (Tph) cells, as opposed to classical Th1 cells. These findings provide a roadmap explaining how T cell responses necessary for control of an infection can, despite antibiotic therapy, drive a disadvantageous T cell response, resulting in a postinfectious, inflammatory arthritis., Wider Recognition of ARLA as a postinfectious complication In 1976, Lyme arthritis (LA) was recognized as a separate clinical entity because of geographic clustering of children in the Lyme Connecticut [...]

Abstract Objective: This study aimed to evaluate the knowledge, attitudes and practices of healthcare providers regarding asplenic patients and to assess their satisfaction with the Victorian Spleen Registry (VSR) service. Methods: Survey forms were sent to 992 healthcare providers listed as caring for at least one patient registered on the VSR. Results: A total of 223 completed questionnaires were returned. Healthcare providers heard about the VSR mainly from another healthcare professional or through a healthcare institution (31.7%), via online or printed resources (30.8%) or from their patients (24.4%). Most respondents valued the work of the VSR in providing information to healthcare professionals (71.4%), providing a reminder service for vaccinations (66.7%) and providing education to patients (60.5%). Most of those surveyed correctly identified high‐risk infections for asplenic and hyposplenic patients with encapsulated organisms, but less than one‐third identified a risk with malarial infections (32.9%). Providers always recommended influenza vaccinations, emergency standby antibiotics and an alert medallion or card in 92.8%, 63.6% and 36.4% of cases, respectively. Conclusions: Healthcare providers value and are satisfied with the service provided by the VSR. Patients can play a valuable role in communicating with their health providers. This survey may have been of value to healthcare providers by heightening awareness of the VSR website as well as knowledge of the registry. Implications: The results positively reflect the functioning of the VSR, although better promotion of the VSR among healthcare professionals and consideration of expansion is needed.

Permafrost underlies approximately one quarter of Northern Hemisphere terrestrial surfaces and contains 25-50% of the global soil carbon (C) pool. Permafrost soils and the C stocks within are vulnerable to ongoing and future projected climate warming. The biogeography of microbial communities inhabiting permafrost has not been examined beyond a small number of sites focused on local-scale variation. Permafrost is different from other soils. Perennially frozen conditions in permafrost dictate that microbial communities do not turn over quickly, thus possibly providing strong linkages to past environments. Thus, the factors structuring the composition and function of microbial communities may differ from patterns observed in other terrestrial environments. Here, we analyzed 133 permafrost metagenomes from North America, Europe, and Asia. Permafrost biodiversity and taxonomic distribution varied in relation to pH, latitude and soil depth. The distribution of genes differed by latitude, soil depth, age, and pH. Genes that were the most highly variable across all sites were associated with energy metabolism and C-assimilation. Specifically, methanogenesis, fermentation, nitrate reduction, and replenishment of citric acid cycle intermediates. This suggests that adaptations to energy acquisition and substrate availability are among some of the strongest selective pressures shaping permafrost microbial communities. The spatial variation in metabolic potential has primed communities for specific biogeochemical processes as soils thaw due to climate change, which could cause regional- to global- scale variation in C and nitrogen processing and greenhouse gas emissions.

We have developed an influenza hemagglutinin protein microarray to assess humoral recognition of diverse influenza strains induced by vaccination and infection. Each array consists of controls and 127 hemagglutinin antigens from 60 viruses, spotted in replicates to generate a single array of 1296 spots. Six arrays are configured on a single slide, which in the following analysis was probed simultaneously with 2 isotype-specific fluorescent secondary antibodies yielding over 15,000 data points per slide. Here we report the use of this system to evaluate mouse, ferret, and human sera. The array allows simultaneous examination of the magnitude of antibody responses, the isotype of such antibodies, and the breadth of influenza strain recognition. We are advancing this technology as a platform for rapid, simple, high-throughput assessment of homologous and heterologous antibody responses to influenza disease and vaccination.

Gunter De Win,1,2 Siska Van Bruwaene,1 Christopher Allen,3 Dirk De Ridder2 1Centre for Surgical Technologies, 2Department of Urology, University Hospitals, KU Leuven, Leuven, Belgium; 3School of Arts and Sciences, University of Pennsylvania, PA, USA Background: Surgical simulation is becoming increasingly important in surgical education. Despite the important work done on simulators, simulator model development, and simulator assessment methodologies, there is a need for development of integrated simulators in the curriculum. In this paper, we describe the design of our evidence-based preclinical training program for medical students applying for a surgical career at the Centre for Surgical Technologies. Methods: Twenty-two students participated in this training program. During their final months as medical students, they received structured, proficiency-based endoscopy training. The total amount of mentored training was 18 hours and the training was organized into three training blocks. The first block focused on psychomotor training, the second block focused on laparoscopic stitching and suturing, and the third block on laparoscopic dissection techniques and hemostasis. Deliberate practice was allowed and students had to show proficiency before proceeding to the next training block. Students’ psychomotor abilities were tested before the course and after each training block. At the beginning of their careers as surgical registrars, their performance on a laparoscopic suturing task was compared with that of registrars from the previous year who did not have this training course. Student opinions about this course were evaluated using a visual analog scale. Results: All students rated the training course as useful and their psychomotor abilities improved markedly. All students performed deliberate practice, and those who participated in this course scored significantly (P < 0.0001) better on the laparoscopic suturing task than first year registrars who did not participate in this course. Conclusion: Organization of a structured preclinical training program in laparoscopy for final year medical students is feasible, attractive, and successful. Keywords: laparoscopy training, proficiency based, surgical skill evaluation, curriculum development

Abstract Objectives While bacterial meningitis is a concerning complication after endoscopic skull base surgery, the diagnosis can be made without consideration for aseptic meningitis. This article aims to (1) present a patient with recurrent craniopharyngioma and multiple postoperative episodes of aseptic meningitis and (2) discuss the diagnosis and management of aseptic meningitis. Design Case report and literature review. Results A 65-year-old female patient with a symptomatic craniopharyngioma underwent transsphenoidal resection. She returned postoperatively with symptoms concerning for cerebrospinal fluid (CSF) leak and bacterial meningitis. Lumbar puncture demonstrated mildly elevated leukocytes with normal glucose levels. Cultures were sterile and she was discharged on antibiotics. She returned 18 days postoperatively with altered mental status and fever. Again, negative CSF cultures suggested aseptic meningitis. Radiological and intraoperative findings were now concerning for widespread cerebrovascular vasospasm due to leaked craniopharyngioma fluids. In the following months, her craniopharyngioma recurred and required multiple surgical resections. Days after her last operation, she returned with mental status changes and a sterile CSF culture. She was diagnosed with recurrent aseptic meningitis and antibiotics were discontinued. The patient experienced near complete resolution of symptoms. Conclusions Consideration of aseptic meningitis following craniopharyngioma resection is critical to avoid unnecessary surgical re-exploration and prolonged courses of antibiotics.

ABSTRACT Despite known low sensitivity, culture of periprosthetic tissue specimens on agars and in broths is routine. Culture of periprosthetic tissue samples in blood culture bottles (BCBs) is potentially more convenient, but it has been evaluated in a limited way and has not been widely adopted. The aim of this study was to compare the sensitivity and specificity of inoculation of periprosthetic tissue specimens into blood culture bottles with standard agar and thioglycolate broth culture, applying Bayesian latent class modeling (LCM) in addition to applying the Infectious Diseases Society of America (IDSA) criteria for prosthetic joint infection. This prospective cohort study was conducted over a 9-month period (August 2013 to April 2014) at the Mayo Clinic, Rochester, MN, and included all consecutive patients undergoing revision arthroplasty. Overall, 369 subjects were studied; 117 (32%) met IDSA criteria for prosthetic joint infection, and 82% had late chronic infection. Applying LCM, inoculation of tissues into BCBs was associated with a 47% improvement in sensitivity compared to the sensitivity of conventional agar and broth cultures (92.1 versus 62.6%, respectively); this magnitude of change was similar when IDSA criteria were applied (60.7 versus 44.4%, respectively; P = 0.003). The time to microorganism detection was shorter with BCBs than with standard media (P < 0.0001), with aerobic and anaerobic BCBs yielding positive results within a median of 21 and 23 h, respectively. Results of our study demonstrate that the semiautomated method of periprosthetic tissue culture in blood culture bottles is more sensitive than and as specific as agar and thioglycolate broth cultures and yields results faster. IMPORTANCE Prosthetic joint infections are a devastating complication of arthroplasty surgery. Despite this, current microbiological techniques to detect and diagnose infections are imperfect. This study examined a new approach to diagnosing infections, through the inoculation of tissue samples from around the prosthetic joint into blood culture bottles. This study demonstrated that, compared to current laboratory practices, this new technique increased the detection of infection. These findings are important for patient care to allow timely and accurate diagnosis of infection.

Skeletal muscle responds to exercise-induced damage by orchestrating an adaptive process that protects the muscle from damage by subsequent bouts of exercise, a phenomenon called the repeated bout effect (RBE). The mechanisms underlying the RBE are not understood. We hypothesized that an attenuated inflammation response following a repeated bout of lengthening contractions (LC) would be coincidental with a RBE, suggesting a potential relationship. Fourteen men (n=7) and women (n=7) completed 2 bouts of lengthening contractions (LC) separated by 28 days. Muscle biopsies were taken before the first bout (B1) from the non-exercised leg, and from the exercised leg 2- and 27-d post-B1 and 2-d following the second bout (B2). A 29-plex cytokine array identified alterations in inflammatory cytokines. Immunohistochemistry quantified inflammatory cell infiltration and major histocompatibility complex class 1 (MHC-1). Muscle soreness was attenuated in the days following B2 relative to B1, indicating a RBE. Intramuscular monocyte chemoattractant protein (MCP1) and interferon gamma-induced protein 10 (IP10) increased following B2 relative to the pre-exercise sample (7 pg/ml to 52 pg/ml, and 11 pg/ml to 36 pg/ml, respectively p

Fluoroquinolone antimicrobial drugs are highly bioavailable, broad-spectrum agents with activity against gram-negative pathogens, especially those resistant to other classes of antimicrobial drugs. Australia has restricted the use of quinolones in humans through its national pharmaceutical subsidy scheme; and, through regulation, has not permitted the use of quinolones in food-producing animals. As a consequence, resistance to fluoroquinolones in the community has been slow to emerge and has remained at low levels in key pathogens, such as Escherichia coli. In contrast to policies in most other countries, this policy has successfully preserved the utility of this class of antimicrobial drugs for treatment of most infections.

To determine whether frontline health care workers (HCWs) are at greater risk for contracting pandemic (H1N1) 2009 than nonclinical staff, we conducted a study of 231 HCWs and 215 controls. Overall, 79 (17.7%) of 446 had a positive antibody titer by hemagglutination inhibition, with 46 (19.9%) of 231 HCWs and 33 (15.3%) of 215 controls positive (OR 1.37, 95% confidence interval 0.84–2.22). Of 87 participants who provided a second serum sample, 1 showed a 4-fold rise in antibody titer; of 45 patients who had a nose swab sample taken during a respiratory illness, 7 had positive results. Higher numbers of children in a participant’s family and working in an intensive care unit were risk factors for infection; increasing age, working at hospital 2, and wearing gloves were protective factors. This highly exposed group of frontline HCWs was no more likely to contract pandemic (H1N1) 2009 influenza infection than nonclinical staff, which suggests that personal protective measures were adequate in preventing transmission.

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 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.

Strong winter warming has dominated recent patterns of climate change along the Arctic Coastal Plain (ACP) of northern Alaska. The full impact of arctic winters may be best manifest by freshwater ice growth and the extent to which abundant shallow ACP lakes freeze solid with bedfast ice by the end of winter. For example, winter conditions of 2016–17 produced record low extents of bedfast ice across the ACP. In addition to high air temperatures, the causes varied from deep snow accumulation on the Barrow Peninsula to high late season rainfall and lake levels farther east on the ACP. In contrast, the previous winter of 2015–16 was also warm, but low snowpack and high winds caused relatively thick lake ice to develop and corresponding high extents of bedfast ice on the ACP. This recent comparison of extreme variation in lake ice responses between two adjacent regions and years in the context of long-term climate and ice records highlights the complexity associated with weather conditions and climate change in the Arctic. Recent observations of maximum ice thickness (MIT) compared to simulated MIT from Weather Research and Forcing (Polar-WRF) model output show greater departure toward thinner ice than predicted by models, underscoring this uncertainty and the need for sustained observations. Lake ice thickness and the extent of bedfast ice not only indicate the impact of arctic winters, but also directly affect sublake permafrost, winter water supply for industry, and overwinter habitat availability. Therefore, tracking freshwater ice responses provides a comprehensive picture of winter, as well as summer, weather conditions and climate change with implications to broader landscape, ecosystem, and resource responses in the Arctic.

Abstract We explore a new calibration-free approach to biodetection based on whispering gallery modes (WGMs) without a reference measure and relative shifts. Thus, the requirement to keep track of the sensor position is removed, and a freely moving population of fluorophore-doped polystyrene microspheres can now fulfill this role of sensing resonator. Breaking free from fixed surface-based biosensing promotes adhesion between the microsphere sensors and the analytes since both can now be thoroughly mixed. The 70-nm-wide spectrum of green fluorescent microbeads allows us to monitor over 20 WGMs simultaneously without needing evanescent light coupling into the microspheres, hence enabling remote sensing. Since the exact radius of each microsphere is unknown a priori, it requires algorithmic analyses to obtain a reliable result for the refractive index of a solution. We first test our approach with different solutions of alcohol in water obtaining 3 × 10−4 precision on the refractive index at lower concentrations. Then, the solutions of bacterial spores in water yield clear evidence of biodetection in the statistical analysis of WGMs from 50 microspheres. To extend the fluorescence spectral range of our WGM sensors, we present preliminary results on coating microspheres with CdSe/ZnS quantum dots.

Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4-2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.