Using biomarkers to allocate patients in a response-adaptive clinical trial.

In this paper, we discuss a response adaptive randomization method, and why it should be used in clinical trials for rare diseases compared to a randomized controlled trial with equal fixed randomization. The developed method uses a patient's biomarkers to alter the allocation probability to each treatment, in order to emphasize the benefit to the trial population. The method starts with an initial burn-in period of a small number of patients, who with equal probability, are allocated to each treatment. We then use a regression method to predict the best outcome of the next patient, using their biomarkers and the information from the previous patients. This estimated best treatment is assigned to the next patient with high probability. A completed clinical trial for the effect of catumaxomab on the survival of cancer patients is used as an example to demonstrate the use of the method and the differences to a controlled trial with equal allocation. Different regression procedures are investigated and compared to a randomized controlled trial, using efficacy and ethical measures.

Telemedicine visits in an established multidisciplinary central nervous system clinic for radiation oncology and neurosurgery (RADIANS) in a community hospital setting.

OBJECTIVE: To determine the impact of telemedicine visits, compared to in-person visits, on patient satisfaction in an established community hospital-based multidisciplinary central nervous system (CNS) clinic. METHODS: Telemedicine options - virtual visits and teleconferencing - were introduced in July 2020. Both radiation oncologist and neurosurgeon were simultaneously present for the telemedicine visit. Descriptive patient demographics, survey responses, and travel time and distance calculations were analyzed. Satisfaction score was compared to previously published data. RESULTS: A total of twenty-five telemedicine visits (n=22 video; n=3 phone) were completed since July 2020. Patient demographics are as follows: mean age was 59 years (range=22-81), women (9) and men (16), repeat telemedicine visits n=10, malignant CNS disease (17) and benign disease (5). Mean one-way distance traveled was 165.07 miles (median=114; range=0.8-358). Mean roundtrip travel time was estimated at 5h 5min. Mean telemedicine visit duration was 15.3 mins (range=4-46). Mean patient satisfaction score for telemedicine visits was 4.84. CONCLUSION: Patients who opted for the telemedicine visits found them just as effective as in-person visits, saving time and travel costs as well as ensuring patient safety during the current COVID-19 pandemic. The telemedicine visit platform facilitates the multidisciplinary clinic model and should be considered for more widespread utilization (Tab. 3, Fig. 1, Ref. 18).

How accurately is hospital acquired pneumonia documented for the correct assignment of a hospital acquired complication (HAC)?

BACKGROUND: In 2016, the Australian Commission on Safety and Quality in Healthcare (ACSQHC) released a list of 16 categories of potentially preventable, high impact hospital-acquired complications (HAC) identified by using administrative coded data (ACD). An important category are hospital-acquired infections (HAI). Within this category, hospital-acquired pneumonia (HAP) is among the most frequent complications documented. There are no published studies concerning the current ACSQHC approach to HAI surveillance using ACD and no pneumonia-specific ACD studies reported from Australia. Published work indicates that ACD detection of HAP has low a sensitivity and positive predictive value (PPV). The current study was designed to examine whether coders correctly reflected the documentation of HAP that was present in the medical record and also evaluated the medical documentation that was present. METHODS: One hundred patients with ACD encoded HAP were selected for review, drawn from admissions to 2 Hunter New England Health hospitals during 2017. Patient records and the eMR were reviewed by two medical officers to assess medical and radiological documentation of pneumonia. The district coding manager reviewed the accuracy of coding of a subset of 23 cases where medical review had not located documented evidence of HAP. RESULTS: Of the 100 reviewed cases, the median patient age was 75 years (range 0-95 years) with 3% under 16 years of age. Twenty one were intensive care-associated of which 13 were associated with ventilation. In 23 cases the documentation was disputed and a secondary review took place - the coding manager confirmed coding changes in 14 of these 23 cases. CONCLUSIONS: This study found that administrative coded data of HAP, utilizing the ACSQHC method reliably reflected the available documentation with a PPV of 86% (95% binomial exact confidence interval 77-92%), much higher than documented by previous ACD studies. The actual documentation of pneumonia by medical staff frequently used the non-specific term 'lower respiratory infection (LRTI)' which we recommend to be avoided. Radiological confirmation was absent in one third of cases. We recommend the adoption of a medical note template checklist for HAP to prompt clinicians with the accepted diagnostic criteria. We also recommend documenting a reason as to why any antibiotic has been commenced in a hospitalized patient in accord with the ACSQHC Antimicrobial Stewardship Clinical Care Standard.

Development of an In Vitro Model of Inflammatory Cytokine Influences on Intervertebral Disk Cells in 3D Cell Culture Using Activated Macrophage-Like THP-1 Cells.

We developed a new model for evaluation of the influence of proinflammatory cytokines on intervertebral disc cells in a 3D culture based on co-culturing of these cells with activated macrophage-like THP-1 cells. The levels of TNFα, IL-1ß, IL-6, IL-8, IL-10, and IL-12p70 production were assessed by flow cytofluorometry using microspheres. Considerable differences in the level of spontaneous cytokine secretion by normal and degenerated intervertebral disc cells were revealed. A significant increase in the level of IL-1ß and IL-8 was observed during co-culturing, which confirms consistency of the developed model.

Risk of persistent or recurrent cervical neoplasia in patients with 'pure' adenocarcinoma-in-situ (AIS) or mixed AIS and high-grade cervical squamous neoplasia (cervical intra-epithelial neoplasia grades 2 and 3 (CIN 2/3)): a population-based study.

OBJECTIVE: To compare outcomes of patients with pure adenocarcinoma-in-situ (AIS) and mixed AIS/CIN 2/3 lesions including the incidence of AIS persistence, recurrence and progression to adenocarcinoma. DESIGN: Retrospective cohort study. SETTING: Statewide population in Western Australia. POPULATION: Women diagnosed with AIS between 2001 and 2012. METHODS: We conducted a retrospective, population-based cohort study. MAIN OUTCOME MEASURES: De-identified linked data were utilised to ascertain the association between patient age at excisional treatment, margin status, lesion type, lesion size, and risk of persistent AIS (defined as the presence of AIS <12 months from treatment), recurrent AIS (≥12 months post-treatment), and adenocarcinoma. RESULTS: 636 patients were eligible for analysis. The mean age was 32.3 years and median follow-up interval was 2.5 years. Within the study cohort, 266 patients (41.8%) had pure AIS and 370 (58.2%) had mixed AIS/CIN 2/3. Overall, 47 patients (7.4%) had AIS persistence/recurrence and 12 (1.9%) had adenocarcinoma. Factors associated with persistence/recurrence were pure AIS (hazard ratio (HR) 2.3; 95%CI 1.28-3.94; P = 0.005), age >30 years (HR 2.1; 95%CI 1.16-3.81; P = 0.015), positive endocervical margins (HR 5.8; 95%CI 3.05-10.92; P = <0.001) and AIS lesions >8 mm (HR 2.5; 95%CI 1.00-6.20; P = 0.049). A histologically positive AIS ectocervical margin was not associated with persistence/recurrence. CONCLUSION: In this study, pure AIS was associated with greater risk of persistence/recurrence than was mixed AIS/CIN 2/3. AIS lesions >8 mm and positive endocervical margins were significant predictors for persistent or recurrent disease. TWEETABLE ABSTRACT: Pure cervical adenocarcinoma-in-situ (AIS) may have greater risk of recurrence than AIS co-existing with CIN 2/3.

Prenatal toluene exposure impairs performance in the Morris Water Maze in adolescent rats.

Volatile organic solvent abuse continues to be a worldwide health problem, including the neurobehavioral teratogenic sequelae of toluene abuse during pregnancy. Although abuse levels of prenatal toluene exposure can lead to a Fetal Solvent Syndrome, there is little research examining these effects on memory. Consumption of toluene can have detrimental effects on the developing hippocampus which could lead to specific spatial learning and memory deficits. This study used a rat model to determine how prenatal exposure to abuse levels of toluene would affect performance in a spatial learning and memory task, the Morris Water Maze (MWM). Pregnant Sprague-Dawley rats were exposed to 0, 8000 or 12,000ppm (ppm) of toluene for 15min twice daily from gestation day 8 (GD8) through GD20. Male and female offspring (N=104) were observed in the MWM for 5days beginning on postnatal day (PN) 28 and again on PN44. While prenatal toluene-exposed animals did not differ in initial acquisition in the MWM, rats prenatally exposed to 12,000ppm toluene displayed performance deficits during a probe trial and in reversal learning on PN44. Overall, this study indicates that prenatal exposure to repeated inhaled abuse patterns of high concentrations of toluene can impair spatial memory function that persists into adolescence.

Changes in developmental body weight as a function of toluene exposure: A meta-analysis of animal studies.

Inhalant abuse is a globally prevalent health issue with particular concerns about substance-abusing pregnant women. In both animal models and clinical case reports of toluene exposure, the primary physiological outcome measure of prenatal inhalant exposure is low birth weight (BW). However, the effect of prenatal toluene exposure on animal BW varies widely in the literature. To clarify this effect and investigate possible design moderators of pup BW, a systematic review and meta-analytic techniques were applied to the existing peer-reviewed animal literature of prenatal and postnatal exposure models to the inhaled solvent toluene. Of 288 studies screened, 24 studies satisfied the inclusion criteria. Evaluation of these studies indicated that toluene exposure was negatively associated with pup BW (d = -0.39), with external inhaled concentration, route of administration, day of weighing, and toluene exposure magnitude moderating this association. Investigators doing animal studies should be cognizant of these factors before investigating the reproductive and developmental outcomes associated with prenatal and postnatal toluene exposure.

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study.

Effective positron emission tomography / computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [(18)F]FDG. The lung lesion insert was driven by six different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses, and 2%-2 mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10-20%, treatment planning errors were 5-10%, and treatment delivery errors were 5-30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5-10% in PET/CT imaging, <5% in treatment planning, and <2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery.

Separating analgesia from reward within the ventral tegmental area.

Activation of the dopaminergic mesolimbic reward circuit that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress emotional responses to noxious stimuli, and presumably contributes to the addictive liability of strong analgesics. VTA dopamine neurons are activated via cholinergic afferents and microinjection of carbachol (cholinergic agonist) into VTA is rewarding. Here, we evaluated regional differences within VTA in the capacity of carbachol to suppress rats' affective response to pain (vocalization afterdischarges, VADs) and to support conditioned place preference (CPP) learning. As carbachol is a non-specific agonist, muscarinic and nicotinic receptor involvement was assessed by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into VTA prior to carbachol treatment. Unilateral injections of carbachol (4µg) into anterior VTA (aVTA) and posterior VTA (pVTA) suppressed VADs and supported CPP; whereas, injections into midVTA failed to effect either VADs or CPP. These findings corroborate the hypothesis that the neural substrates underlying affective analgesia and reward overlap. However, the extent of the overlap was only partial. Whereas both nicotinic and muscarinic receptors contributed to carbachol-induced affective analgesia in aVTA, only muscarinic receptors mediated the analgesic action of carbachol in pVTA. The rewarding effects of carbachol are mediated by the activation of both nicotinic and muscarinic receptors in both aVTA and pVTA. The results indicate that analgesia and reward are mediated by separate cholinergic mechanisms within pVTA. Nicotinic receptor antagonism within pVTA failed to attenuate carbachol-induced analgesia, but prevented carbachol-induced reward. As addictive liability of analgesics stem from their rewarding properties, the present findings suggest that these processes can be neuropharmacologically separated within pVTA.

Can UK healthcare workers remotely support medical education in the developing world?: Focus group evaluation.

OBJECTIVES: To evaluate the feasibility of providing regular, live, text-based teaching to medical students and junior doctors in Somaliland using a dedicated case-based medical education website (www.MedicineAfrica.com). DESIGN: Review of MedicineAfrica database for details of teaching sessions held in Somaliland from December 2008-October 2010 and evaluation of user experiences through focus groups. SETTING: King's College Hospital, London, UK and Ahmoud University, Borama, Somaliland. PARTICIPANTS: Final year medical students, newly graduated interns and second year interns at Ahmoud University, Borama, Somaliland. MAIN OUTCOME MEASURES: Qualitative and quantitative user rating of online case-based tutorials in the context of pre-existing educational opportunities available to them. RESULTS: Regular online teaching sessions are received enthusiastically by students and junior doctors and are reported to improve their clinical practice. CONCLUSIONS: Despite technological limitations in Somaliland, a live text-based teaching service can be delivered effectively and streamlined with local curricula. This represents an alternative to traditional static teaching methodologies currently used in international medical education.

A rapid access diagnostic clinic for prostate cancer: the experience after one year.

BACKGROUND: The National Cancer Control Programme is developing standards for access to diagnostics and treatment of prostate cancer. The Rapid Access Prostate Cancer (RAPC) clinic in St. James's Hospital commenced in May 2009 allowing general practitioners (GPs) more streamlined access for patients. AIMS: To demonstrate that RAPC clinics allow GPs direct access to a designated cancer centre improving the prostate cancer referral process. This ultimately should reduce referral delays. METHODS: A prospective analysis of all patients referred to the RAPC clinic in St. James's Hospital over a 12-month period beginning from May 2009. RESULTS: Over the 12-month period 215 patients were referred to the RAPC clinic. The median age was 63 years (range 45-78). The median waiting time between referral and review at the RAPC clinic was 13 days (range 1-37). The median PSA was 7.7 µg/L (range 2.6-150). In total 199 TRUS biopsies were performed, of which 46% were positive for prostate cancer. We found that 70% of all patients had a PSA ≤ 10 µg/L and of these 32% were positive for prostate cancer. For the remaining 30% of patients who had a PSA > 10 µg/L, we found 63% were positive for prostate cancer. Regarding patients diagnosed with prostate cancer 56% have been referred for radiotherapy, 13% for surgery, 13% for hormonal treatment, 10% for active surveillance and 8% watchful waiting. CONCLUSION: RAPC clinics allow GPs easier access to specialist urological opinion for patients suspected of having prostate cancer.

Cancer--we're here to listen.

The National Cancer Forum (2006) recommended that high-quality efficient information resources should be made available to the public. In order to address the needs of the public, the Irish Cancer Society provide a national Cancer Information Service (CIS) incorporating a Prostate Cancer Information Service (PCIS). This audit was designed to explore the information and support needs of those who contacted the Irish Cancer Society's information services during 2007.

WITHDRAWN: Neurobehavioral effects of repeated binge toluene exposure as measured by a waiting-for-reward operant task.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

A decade of public health genomics in the United States: centers for disease control and prevention 1997-2007.

Since 1997, the Centers for Disease Control and Prevention (CDC) has collaborated with numerous partners to develop and chart the course of the multidisciplinary field of public health genomics in the USA and globally. During this period, CDC has developed major initiatives for the appropriate integration of genomics into public health research, policy and programs. In this paper, we review briefly the progress in public health genomics made over the past decade in the USA, including population research, the human genome epidemiology network (HuGENet(TM)), the evaluation of genomic applications in practice and prevention (EGAPP), the family history public health initiative, and efforts in building the public health genomics capacity. We also outline a vision for public health genomics for the next decade.

Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis.

A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.

Outbreak of invasive methicillin-resistant Staphylococcus aureus infection associated with acupuncture and joint injection.

OBJECTIVE: To describe an outbreak of invasive methicillin-resistant Staphylococcus aureus (MRSA) infection after percutaneous needle procedures (acupuncture and joint injection) performed by a single medical practitioner. SETTING: A medical practitioner's office and 4 hospitals in Perth, Western Australia. PATIENTS: Eight individuals who developed invasive MRSA infection after acupuncture or joint injection performed by the medical practitioner. METHODS: We performed a prospective and retrospective outbreak investigation, including MRSA colonization surveillance, environmental sampling for MRSA, and detailed molecular typing of MRSA isolates. We performed an infection control audit of the medical practitioner's premises and practices and administered MRSA decolonization therapy to the medical practitioner. RESULTS: Eight cases of invasive MRSA infection were identified. Seven cases occurred as a cluster in May 2004; another case (identified retrospectively) occurred approximately 15 months earlier in February 2003. The primary sites of infection were the neck, shoulder, lower back, and hip: 5 patients had septic arthritis and bursitis, and 3 had pyomyositis; 3 patients had bacteremia, including 1 patient with possible endocarditis. The medical practitioner was found to be colonized with the same MRSA clone [ST22-MRSA-IV (EMRSA-15)] at 2 time points: shortly after the first case of infection in March 2003 and again in May 2004. After the medical practitioner's premises and practices were audited and he himself received MRSA decolonization therapy, no further cases were identified. CONCLUSIONS: This outbreak most likely resulted from a breakdown in sterile technique during percutaneous needle procedures, resulting in the transmission of MRSA from the medical practitioner to the patients. This report demonstrates the importance of surveillance and molecular typing in the identification and control of outbreaks of MRSA infection.

Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells.

Brn-3b transcription factor enhances proliferation of neuroblastoma (NB) and breast cancer cell lines in vitro and increases the rate and size of in vivo tumour growth, whereas reducing Brn-3b slows growth, both in vitro and in vivo. Brn-3b is elevated in >65% of breast cancer biopsies, and here we demonstrate that Brn-3b is also elevated in NB tumours. We show a significant correlation between Brn-3b and cyclin D1 (CD1) in breast cancers and NB tumours and cell lines. Brn-3b directly transactivates the CD1 promoter in co-transfection experiments, whereas electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrate that Brn-3b protein binds to an octamer sequence located in the proximal CD1 promoter. Site-directed mutagenesis of this sequence resulted in loss of transactivation of the CD1 promoter by Brn-3b. Thus, Brn-3b may act to alter growth properties of breast cancer and NB cells by enhancing CD1 expression in these cells.

PTSD symptoms, substance use, and vipassana meditation among incarcerated individuals.

The present study evaluated whether Posttraumatic Stress Disorder (PTSD) symptom severity was associated with participation and treatment outcomes comparing a Vipassana meditation course to treatment as usual in an incarcerated sample. This study utilizes secondary data. The original study demonstrated that Vipassana meditation is associated with reductions in substance use. The present study found that PTSD symptom severity did not differ significantly between those who did and did not volunteer to take the course. Participation in the Vipassana course was associated with significantly greater reductions in substance use than treatment as usual, regardless of PTSD symptom severity levels. These results suggest that Vipassana meditation is worthy of further study for those with comorbid PTSD and substance use problems.

Region-dependent alterations in glutamate and GABA measured by high-resolution magnetic resonance spectroscopy following acute binge inhalation of toluene in juvenile rats.

Little is known about the neurochemical effects accompanying the high-concentration inhalant exposures characteristic of binge solvent abuse. In adult animals, prior studies with other patterns of exposure indicate that toluene, a commonly abused household and industrial solvent, has significant effects on the glutamatergic and GABAergic neurotransmitter systems and on other neurotransmitter systems as well. In the current investigation, high-resolution "magic angle" spinning proton magnetic resonance spectroscopy (HR-MAS (1)H-MRS) was used to assess the effect of acute binge toluene inhalation on regional brain concentrations of various neurochemicals including glutamate (GLU), GABA, and glutamine (GLN) in juvenile male and female rats. Acute toluene (8000 ppm or 12,000 ppm) significantly reduced levels of hippocampal GABA (-12%) and GLU (-8%), and the GLU/GLN ratio, an index of glutamatergic tone, was significantly reduced (-22%) in the dorsal anterior striatum, driven largely by a 28% increase in GLN. Significant increases in alanine and lactate in several brain regions after acute toluene may be indicative of altered oxygen-dependent metabolism associated with the inhalation of higher concentrations of toluene (e.g., >5000 ppm). Other components of the MR-visible neurochemical profile, such as N-acetylaspartate (NAA), myo-inositol, creatine, and various choline containing compounds, were unchanged by acute toluene. The results are consistent with the notion that binge toluene exposure affects juvenile neurochemistry in systems mediating the rewarding and emotional aspects of substance abuse. Moreover the results provide a framework to understand further (1)H-MRS studies in clinical populations.