Concurrent nonavalent human papillomavirus (HPV) vaccination and immune stimulation with imiquimod to treat recalcitrant HPV-associated high grade vaginal intra-epithelial neoplasia.

This is the first report describing detailed T cell responses to viral-like proteins contained in an HPV specific vaccine given in combination with Imiquimod for treatment of persistent VAIN2/3. We postulate that stimulation of the innate immune system with Imiquimod and the specific CD4 and CD8T cell responses following HPV vaccination with Gardasil9@ combined to induce clinical remission in a woman with treatment-refractory disease.

Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer in an Australian institution: lessons from 20 years' experience.

OBJECTIVES: We report the 20-year experience of the largest Australian unit performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer and reflect on learning opportunities. METHODS: A retrospective review of all cases of CRS for ovarian cancer at St George Peritonectomy Unit from Jan 1998 to Jan 2018 was performed. Prospectively collected data include age, stage, histology, disease extent (PCI), completeness of cytoreduction (CC score), HIPEC regime, 30-day surgical morbidity, disease recurrence, and death. Survival was computed using Kaplan-Meier method and analysed using log-rank tests and Cox-proportional hazards models. RESULTS: Forty-one women with advanced ovarian cancer (11 primary stage III/IV, 30 recurrent) underwent CRS, 29 (71%) with HIPEC. Most (68%) had high-volume disease (PCI > 15). In 98%, CC0/CC1 (residual < 2.5 mm) was achieved. Fourteen (34%) had grade 3/4 complications, 1 patient (2%) died within 30 days and 2 patients (5%) died within 90 days. Progression-free and median overall survival was 30.0 and 67.0 months for primary cancer, and 6.7 and 18.1 months for recurrent cancer. Survival was associated with platinum-sensitivity, PCI ≤ 15, and CC score 0, but not HIPEC. CONCLUSION: This study reports outcomes for patients with advanced ovarian cancer patients treated in an Australian centre offering CRS and HIPEC. Whilst survival and morbidity outcomes were good for primary disease, they were poorer than predicted from the literature for cases of recurrent disease. The incorporation of evidence-based predictors of survival and multidisciplinary input are essential to achieve the best survival outcomes.

Evaluation of the cognitive benefits of intrathecal baclofen pump implantation in people with intractable multiple sclerosis related spasticity.

BACKGROUND: Spasticity is a common problematic symptom in Multiple Sclerosis with over one third of patients failing first line therapies. Intrathecal baclofen is a safe and efficacious option for treatment resistant spasticity. Anecdotally patients report improved concentration/cognitive performance when switching to intrathecal baclofen (ITB) from systemic medications. AIM: To explore whether subjects who proceed with ITB pump implantation for spasticity management and reduce oral anti-spasticity agents will have improved cognitive function. METHODS: Subjects were admitted for trial of ITB via lumbar puncture and subsequent pump implantation. Spasticity and cognitive measures before ITB trial and 3 months post implant were recorded. Paired t-test or Wilcoxon Signed Ranks test was used for within subject change and effect sizes (Cohen's dz) were calculated. Subgroup analysis of those on ≥2, or ≤ 1 spasticity medications at baseline was performed. RESULTS: 27 subjects with MS completed per protocol. Mean age 46 years [26 - 56], disease duration 15 years [6 - 26], RRMS = 3, SPMS = 17 and PPMS=7. The majority were on multiple spasticity medications. Spasticity scores significantly improved post pump implant. Mean ITB dose at 3 months was 143 mcg / day and 19 discontinued all other treatments for spasticity. There was no deterioration on any cognitive or mood measure. An improvement of moderate effect size was found in Backwards Digit Span (d=0.41, p=0.059) and HADS - anxiety (d=0.37, p=0.097). Fatigue Severity Scale score decreased substantially (d=0.81, p=0.005). Small improvements in Symbol Digit Modalities Test score (d=0.24) and Sustained Attention to Response Task response time (d=0.23) were non-significant. Performance on other measures did not change. Effect sizes were larger in subgroup on ≥2 oral spasticity medications at baseline, compared to the group on ≤1 medication (SDMT, d=0.42 vs d=0.07; Backwards digit span 0.45 vs 0.28; HADS-anxiety 0.39 vs 0.32; HADS-depression d=0.32 vs 0.05 and FSS, d= 1.14 vs 0.42). CONCLUSIONS: In a pilot study exploring the impact of ITB on cognition, spasticity scores improved universally and beneficial effects on some measures of fatigue, anxiety, auditory attention and verbal working memory were found. Improvement of speed of processing in those withdrawing higher doses of oral medication was also demonstrated suggesting that switching to ITB has added cognitive and psychological benefits for people with MS.

Evaluation of the impact of intrathecal baclofen on the walking ability of people with Multiple Sclerosis related spasticity.

BACKGROUND: Spasticity is a frequent and disabling symptom in people with Multiple Sclerosis (MS). Intrathecal baclofen (ITB) is an effective but infrequently used treatment in ambulant people. OBJECTIVE: To evaluate the impact of ITB on ambulation in people with moderate to severe MS related spasticity. METHODS: Data was collected prospectively regarding spasticity and ambulation at baseline, after ITB trial via lumbar puncture, 3 months and annually thereafter. RESULTS: 30 subjects; Mean age 47.9 (26-64), 67% female, mean EDSS 6.5 [6.5-7.5]. Reduction in mean Ashworth score (pre 1.44: post 0.98, p<0.001) and Penn spasm score (pre 3: post 1; p<0.001) was shown. 20 people (67%) proceeded with implantation; lower limb MRC power was predictive of proceeding to pump (OR 2.98; 95% CI 1.01 - 8.7; p <0.05). In those proceeding to implantation there was no difference in 10mTW at 1 year (ANOVA (F(3,24) = 2.6, p=0.13). Currently, 15 (75%) remain ambulatory (mean 3.75 years, range 1-9). After implant, 17 (85%) discontinued all oral anti-spasticity treatments conferring other benefits. CONCLUSION: Ambulation in people with MS can be preserved for several years whilst effectively treating spasticity with ITB with careful patient selection; ITB should not be considered a last resort.

Neonatal organ donation: Ethical insights and policy implications.

In the realm of clinical ethics as well as in health policy and organizational ethics, the onus of our work as ethicists is to optimize the medical care and experience of the patient to better target ethical dilemmas that develop in the course of care delivery. The role of ethics is critical in all aspects of medicine, but particularly so in the difficult and often challenging cases that arise in the care of pregnant women and newborns. One exemplary situation is that when a pregnant woman and her partner consider neonatal organ donation after receiving news of a terminal diagnosis and expected death of the newborn. While a newer, less practiced form of organ donation, this approach is gaining greater visibility as an option for parents facing this terminal outcome. The aim of our paper is to highlight some of the key ethical issues associated with neonatal organ donation and identify clinical and logistical aspects of implementing such an approach to facilitate organ donation.

Combination of infliximab with thiopurines significantly reduces white cell and neutrophil counts in inflammatory bowel disease patients.

BACKGROUND: The effects of thiopurines on white cell count are well documented. OBJECTIVE: We compared the effects of infliximab 5 mg/kg monotherapy and combination of infliximab with thiopurines on the total and differential white cell count (WBC). METHODS: 13 IBD patients treated with infliximab monotherapy and 18 IBD patients treated with a combination of infliximab and thiopurines were included in the study. Using retrospective data, cell counts were examined prior to induction of infliximab, and at 6 weeks and 1 year post-induction. RESULTS: The patients on combination therapy had an absolute WBC at 52 weeks of 5.7 whereas that of patients on Infliximab monotherapy at the same time point was 8.3 with comparable neutrophil count of 3.4 and 5.4. The results showed a significant reduction in white cell count and neutrophils at 6 weeks which persisted at 52 weeks in both groups (p < 0.05) with a greater drop in patients on combination infliximab and thiopurine (p < 0.05) as compared to Infliximab monotherapy. There was no significant change in the lymphocyte count. CONCLUSION: Full blood counts should be closely monitored in all patients starting infliximab therapy, in particular patients receiving concomitant thiopurines.

Listeria meningitis complicating a patient with ulcerative colitis on concomitant infliximab and hydrocortisone.

Infliximab, a monoclonal antibody directed against tumour necrosis factor, is an effective therapy for moderate-to-severe ulcerative colitis and Crohn's disease. Uncommonly, serious opportunistic infections have occurred in patients after infliximab administration. Here, we describe meningitis caused by Listeria monocytogenes developing in a 37-year-old man with ulcerative colitis refractory to intravenous corticosteroids 10 days after receiving his first infusion of infliximab. With the increasing use of tumour necrosis factor-α-neutralizing agents, clinicians should be aware of the risk of opportunistic infections caused by L. monocytogenes in patients with inflammatory bowel disease following infliximab treatment. The half-life of infliximab is 9.5 days; therefore, patients tend to be more susceptible in the immediate period following infusion. Patients receiving anti-TNF therapy should be advised to avoid foods such as soft cheeses and unpasteurized dairy products.

Plasmonic gold nanostars for multi-modality sensing and diagnostics.

Gold nanostars (AuNSs) are unique systems that can provide a novel multifunctional nanoplatform for molecular sensing and diagnostics. The plasmonic absorption band of AuNSs can be tuned to the near infrared spectral range, often referred to as the "tissue optical window", where light exhibits minimal absorption and deep penetration in tissue. AuNSs have been applied for detecting disease biomarkers and for biomedical imaging using multi-modality methods including surface-enhanced Raman scattering (SERS), two-photon photoluminescence (TPL), magnetic resonance imaging (MRI), positron emission tomography (PET), and X-ray computer tomography (CT) imaging. In this paper, we provide an overview of the recent development of plasmonic AuNSs in our laboratory for biomedical applications and highlight their potential for future translational medicine as a multifunctional nanoplatform.

What patients are reading about noninvasive prenatal testing: an evaluation of Internet content and implications for patient-centered care.

OBJECTIVE: Patients' use of the Internet as a source of health information is increasing. The objective of this study was to describe and evaluate Internet-based information about noninvasive prenatal testing (NIPT), an important new genetic test currently available to high-risk women in early pregnancy. METHODS: Websites were sampled using leading search engines to mirror Internet-based search patterns of individuals seeking information about NIPT. Content analysis was conducted to assess website reading level, quality, and content. RESULTS: Basic information about NIPT use as a screening test was accurately described. Overall, sampled websites lacked balance and comprehensive information about NIPT and the complexity of decision making involved in electing for its use. All websites were written at reading levels higher than currently recommended levels for public health information. CONCLUSION: While online resources should be used with reservation, they can be an important tool to support effective communication and patient-centered care. Online information can help both health care providers and pregnant patients who face a growing number of fetal genetic testing options.

Use of outpatient parenteral antimicrobial therapy for transrectal ultrasound-guided prostate biopsy prophylaxis in the setting of community-associated multidrug-resistant Escherichia coli rectal colonization.

OBJECTIVE: To study the use of ertapenem delivered in an outpatient parenteral antimicrobial therapy (OPAT) hospital-based unit setting for targeted transrectal ultrasound-guided prostate biopsy (TRUSPBx) prophylaxis in the setting of multidrug-resistant (MDR) Escherichia coli rectal colonization. E coli is the pathogen most commonly associated with post-TRUSPBx complications, and there is increasing prevalence of community-associated MDR E coli. METHODS: Prospective data analysis of all patients admitted to the OPAT unit for administration of intravenous antibiotics for prophylaxis for TRUSPBx over 18-month period was performed. Patients had identification of MDR E coli in rectal swab cultures and/or intolerance to available oral agents. Microbiologic data and tolerability of administered antibiotics and outcome after TRUSPBx were tabulated. RESULTS: Nine patients (median age 74 years) were referred because of antibiotic-resistant E coli from rectal swabs (all fluoroquinolone resistant, 7 MDR). All patients received ertapenem 1 g intravenously 1 day before TRUSPBx and the day of the procedure before TRUSPBx. None of the patients experienced infectious complications immediately after TRUSPBx or several weeks or months later, and no patient was lost to urologic follow-up. CONCLUSION: Increasing worldwide reports of prostatitis, urinary tract infections, and septicemia after TRUSPBx because of MDR E coli suggest rectal screening before procedure may be useful in decreasing complications. Targeted prophylaxis in these instances is necessary. Although carbapenems are used for treatment, they are not routinely used for prophylaxis. We report successful use of ertapenem delivered in a hospital-based OPAT unit for TRUSPBx prophylaxis.

Betabox: a beta particle imaging system based on a position sensitive avalanche photodiode.

A beta camera has been developed that allows planar imaging of the spatial and temporal distribution of beta particles using a 14 × 14 mm(2) position sensitive avalanche photodiode (PSAPD). This camera system, which we call Betabox, can be directly coupled to microfluidic chips designed for cell incubation or other biological applications. Betabox allows for imaging the cellular uptake of molecular imaging probes labeled with charged particle emitters such as (18)F inside these chips. In this work, we investigate the quantitative imaging capabilities of Betabox for (18)F beta particles, in terms of background rate, efficiency, spatial resolution, and count rate. Measurements of background and spatial resolution are considered both at room temperature (21 °C ± 1 °C) and at an elevated operating temperature (37 °C ± 1 °C), as is often required for biological assays. The background rate measured with a 4 keV energy cutoff is below 2 cph mm(-2) at both 21 and 37 °C. The absolute efficiency of Betabox for the detection of (18)F positron sources in contact with a PSAPD with the surface passivated from ambient light and damage is 46% ± 1%. The lower detection limit is estimated using the Rose Criterion to be 0.2 cps mm(-2) for 1 min acquisitions and a 62 × 62 µm(2) pixel size. The upper detection limit is approximately 21 000 cps. The spatial resolution at both 21 and 37 °C ranges from 0.4 mm FWHM at the center of the field of view (FOV), and degrades to 1 mm at a distance of 5 mm away from center yielding a useful FOV of approximately 10 × 10 mm(2). We also investigate the effects on spatial resolution and sensitivity that result from the use of a polymer based microfluidic chip. For these studies we place varying layers of low-density polyethylene (LDPE) between the detector and the source and find that the spatial resolution degrades by ∼180 µm for every 100 µm of LDPE film. Sensitivity is reduced by half with the inclusion of ∼200 µm of additional LDPE film. Lastly, we demonstrate the practical utilization of Betabox, with an imaging test of its linearity, when coupled to a polydimethylsiloxane microfluidic chip designed for cell based assays.

Safety trial of Floseal(®) haemostatic agent in head and neck surgery.

INTRODUCTION: Floseal(®) can be of value in reducing blood loss and haematoma rates. The manufacturer's warnings include allergic reaction, poor wound healing and intravascular thrombosis. We aimed to determine whether Floseal(®) is safe to use in various head and neck surgery procedures. METHODS: A prospective trial was conducted using Floseal(®) in 42 various consecutive head and neck surgery procedures. Adverse incidents were used as the main outcome measure, including allergic reaction, wound breakdown, wound infection and thrombosis. Secondary outcome measures included haematoma formation, hospital stay, drain times and output. RESULTS: No adverse incidents were recorded in the trial period. Two patients developed haematomas and required surgical exploration where a bleeding vessel was identified and dealt with. CONCLUSIONS: Floseal(®) is safe to be used in head and neck surgery with no adverse effects. A larger number and a control group are required to ascertain its value in reducing blood loss, haematoma formation, drain usage and hospital stay.

Response of large area avalanche photodiodes to low energy x rays.

For an experiment to study neutron radiative beta-decay, we operated large area avalanche photodiodes (APDs) near liquid nitrogen temperature to detect x rays with energies between 0.2 keV and 20 keV. Whereas there are numerous reports of x ray spectrometry using APDs at energies above 1 keV, operation near liquid nitrogen temperature allowed us to reach a nominal threshold of 0.1 keV. However, due to the short penetration depth of x rays below 1 keV, the pulse height spectrum of the APD become complex. We studied the response using monochromatic x ray beams and employed phenomenological fits of the pulse height spectrum to model the measurement of a continuum spectrum from a synchrotron. In addition, the measured pulse height spectrum was modelled using a profile for the variation in efficiency of collection of photoelectrons with depth into the APD. The best results are obtained with the collection efficiency model.

Effect of aspect ratio and deformability on nanoparticle extravasation through nanopores.

We describe the fabrication of filamentous hydrogel nanoparticles using a unique soft lithography based particle molding process referred to as PRINT (particle replication in nonwetting templates). The nanoparticles possess a constant width of 80 nm, and we varied their lengths ranging from 180 to 5000 nm. In addition to varying the aspect ratio of the particles, the deformability of the particles was tuned by varying the cross-link density within the particle matrix. Size characteristics such as hydrodynamic diameter and persistence length of the particles were analyzed using dynamic light scattering and electron microscopy techniques, respectively, while particle deformability was assessed by atomic force microscopy. Additionally, the ability of the particles to pass through membranes containing 0.2 µm pores was assessed by means of a simple filtration technique, and particle recovery was determined using fluorescence spectroscopy. The results show that particle recovery is mostly independent of aspect ratio at all cross-linker concentrations utilized, with the exception of 96 wt % PEG diacrylate 80 × 5000 nm particles, which showed the lowest percent recovery.

18F-fluorodeoxyglucose positron emission tomography/computed tomography in the assessment of occult primary head and neck cancers--an audit and review of published studies.

AIMS: To assess the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with squamous cell and undifferentiated cancer neck nodes and no primary site on conventional assessment. MATERIALS AND METHODS: Seventy-eight patients with neck nodal metastases from an unknown primary cancer were studied. PET/CT was carried out in all patients, 1h after FDG injection. RESULTS: Uptake suspicious of an occult primary cancer was found in 46/78 (59.0%) patients. Subsequent investigations confirmed a primary site in the base of the tongue in 14, pharyngeal palatine tonsil in 14, post cricoid in one, lung in one. PET/CT diagnosed primary cancers in 30/78 patients (38.5%); sensitivity, specificity, positive predictive value, negative predictive value: 30/30 (100.0%), 32/48 (66.7%), 30/46 (65.2%), 32/32 (100.0%), respectively. PET/CT detected additional disease in four patients: contralateral nodal disease in two, mediastinal nodal disease in one and liver metastases in one. CONCLUSIONS: FDG PET/CT is of value in the assessment of patients with occult head and neck primary cancers. However, false-positive results remain a limitation of the investigation.