BENCHMARKING AND IMPLEMENTATION OF A NEW INDEPENDENT MONTE CARLO DOSE CALCULATION QUALITY ASSURANCE AUDIT TOOL FOR CLINICAL TRIALS

Introduction Commercial treatment planning systems employ a variety of dose calculation algorithms to plan and predict the dose distributions a patient receives during external beam radiation therapy. Traditionally, the Radiological Physics Center has relied on measurements to assure that institutions participating in the National Cancer Institute sponsored clinical trials administer radiation in doses that are clinically comparable to those of other participating institutions. To complement the effort of the RPC, an independent dose calculation tool needs to be developed that will enable a generic method to determine patient dose distributions in three dimensions and to perform retrospective analysis of radiation delivered to patients who enrolled in past clinical trials. Methods A multi-source model representing output for Varian 6 MV and 10 MV photon beams was developed and evaluated. The Monte Carlo algorithm, know as the Dose Planning Method (DPM), was used to perform the dose calculations. The dose calculations were compared to measurements made in a water phantom and in anthropomorphic phantoms. Intensity modulated radiation therapy and stereotactic body radiation therapy techniques were used with the anthropomorphic phantoms. Finally, past patient treatment plans were selected and recalculated using DPM and contrasted against a commercial dose calculation algorithm. Results The multi-source model was validated for the Varian 6 MV and 10 MV photon beams. The benchmark evaluations demonstrated the ability of the model to accurately calculate dose for the Varian 6 MV and the Varian 10 MV source models. The patient calculations proved that the model was reproducible in determining dose under similar conditions described by the benchmark tests. Conclusions The dose calculation tool that relied on a multi-source model approach and used the DPM code to calculate dose was developed, validated, and benchmarked for the Varian 6 MV and 10 MV photon beams. Several patient dose distributions were contrasted against a commercial algorithm to provide a proof of principal to use as an application in monitoring clinical trial activity.

The missing link between clinical states and biomarkers in mental disorders

Current diagnostic definitions of psychiatric disorders based on collections of symptoms encompass very heterogeneous populations and are thus likely to yield spurious results when exploring biological correlates of mental disturbances. It has been suggested that large studies of biomarkers across diagnostic entities may yield improved clinical information. Such a view is based on the concept of assessment as a collection of symptoms devoid of any clinical judgment and interpretation. Yet, important advances have been made in recent years in clinimetrics, the science of clinical judgment. The current clinical taxonomy in psychiatry, which emphasizes reliability at the cost of clinical validity, does not include effects of comorbid conditions, timing of phenomena, rate of progression of an illness, responses to previous treatments, and other clinical distinctions that demarcate major prognostic and therapeutic differences among patients who otherwise seem to be deceptively similar since they share the same psychiatric diagnosis. Clinimetrics may provide the missing link between clinical states and biomarkers in psychiatry, building pathophysiological bridges from clinical manifestations to their neurobiological counterparts.

Owner-reported coughing and nasal discharge are associated with clinical findings, arterial oxygen tension, mucus score and bronchoprovocation in horses with recurrent airway obstruction in a field setting.

REASONS FOR PERFORMING STUDY In clinical practice, veterinarians often depend on owner-reported signs to assess the clinical course of horses with recurrent airway obstruction (RAO). OBJECTIVES To test whether owner-reported information on frequency of coughing and observation of nasal discharge are associated with clinical, cytological and bronchoprovocation findings in RAO-affected horses in nonstandardised field conditions. STUDY DESIGN Cross-sectional study comparing healthy and RAO-affected horses. METHODS Twenty-eight healthy and 34 RAO-affected Swiss Warmblood horses were grouped according to owner-reported 'coughing frequency' and 'nasal discharge'. Differences between these groups were examined using clinical examination, blood gas analyses, endoscopic mucus scores, cytology of tracheobronchial secretion and bronchoalveolar lavage fluid, and airway hyperresponsiveness determined by plethysmography with histamine bronchoprovocation. RESULTS Frequently coughing horses differed most markedly from healthy control animals. Histamine bronchoprovocation-derived parameters were significantly different between the healthy control group and all RAO groups. Mucus grades and tracheobronchial secretion and bronchoalveolar lavage fluid neutrophil percentages had particularly high variability, with overlap of findings between groups. Owner satisfaction with the clinical status of the horse was high, even in severely affected horses. CONCLUSIONS Owner-reported coughing and nasal discharge are associated with specific clinical and diagnostic findings in RAO-affected horses in field settings. While airway hyperresponsiveness differentiates best between healthy horses and asymptomatic RAO-affected horses, the absence of coughing and nasal discharge does not rule out significant neutrophilic airway inflammation. Owner satisfaction with the clinical status of the horse was uninformative.

Campylobacter concisus pseudo-outbreak caused by improved culture conditions.

An unusual increase of Campylobacter concisus in stool cultures provoked an outbreak investigation at the University Hospital of Bern. No epidemiological links were found between cases, and the Campylobacter isolates were clonally unrelated. A change in culture conditions to a hydrogen-rich atmosphere enhancing growth of C. concisus was deemed responsible for this pseudo-outbreak.

Climatic conditions as a risk factor in canine gastric dilatation-volvulus

Canine acute gastric dilatation-volvulus (GDV) is a life-threatening condition of multifactorial origin. The risk of developing GDV is influenced by a variety of factors, including breed, age, gender, temperament, diet and management. A relationship between seasonal variations and the frequency of GDV has been previously documented although no association was found with any specific climatic event. Variables in weather conditions within a defined geographic region were investigated in a retrospective study of 287 client-owned dogs diagnosed with GDV between 1992 and 1999. Monthly incidences were evaluated and differences in atmospheric temperature, humidity and pressure between days in which GDV cases were observed and days in which no case was presented were examined. Although temperature was significantly associated with the occurrence of GDV, the difference in temperatures between days with and days without GDV cases was so small that it is unlikely to be of clinical relevance. Moreover, no significant association was found between GDV occurrence and atmospheric pressure or humidity, and a seasonal variation in GDV incidence was not observed.

A novel multidimensional geriatric screening tool in the ED: evaluation of feasibility and clinical relevance

PURPOSES Geriatric problems frequently go undetected in older patients in emergency departments (EDs), thus increasing their risk of adverse outcomes. We evaluated a novel emergency geriatric screening (EGS) tool designed to detect geriatric problems. BASIC PROCEDURES The EGS tool consisted of short validated instruments used to screen 4 domains (cognition, falls, mobility, and activities of daily living). Emergency geriatric screening was introduced for ED patients 75 years or older throughout a 4-month period. We analyzed the prevalence of abnormal EGS and whether EGS increased the number of EGS-related diagnoses in the ED during the screening, as compared with a preceding control period. MAIN FINDINGS Emergency geriatric screening was performed on 338 (42.5%) of 795 patients presenting during screening. Emergency geriatric screening was unfeasible in 175 patients (22.0%) because of life-threatening conditions and was not performed in 282 (35.5%) for logistical reasons. Emergency geriatric screening took less than 5 minutes to perform in most (85.8%) cases. Among screened patients, 285 (84.3%) had at least 1 abnormal EGS finding. In 270 of these patients, at least 1 abnormal EGS finding did not result in a diagnosis in the ED and was reported for further workup to subsequent care. During screening, 142 patients (42.0%) had at least 1 diagnosis listed within the 4 EGS domains, significantly more than the 29.3% in the control period (odds ratio 1.75; 95% confidence interval, 1.34-2.29; P<.001). Emergency geriatric screening predicted nursing home admission after the in-hospital stay (odds ratio for ≥3 vs <3 abnormal domains 12.13; 95% confidence interval, 2.79-52.72; P=.001). PRINCIPAL CONCLUSIONS The novel EGS is feasible, identifies previously undetected geriatric problems, and predicts determinants of subsequent care.

EPA guidance on the early intervention in clinical high risk states of psychoses

This guidance paper from the European Psychiatric Association (EPA) aims to provide evidence-based recommendations on early intervention in clinical high risk (CHR) states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. Besides analyses on treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n = 1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional provements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates, but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples could have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk Status.

Determination of vertebral range of motion using inertial measurement units in 27 Franches-Montagnes stallions and comparison between conditions and with a mixed population

REASONS FOR PERFORMING STUDY: The diagnosis of equine back disorders is challenging. Objectively determining movement of the vertebral column may therefore be of value in a clinical setting. OBJECTIVES: To establish whether surface-mounted inertial measurement units (IMUs) can be used to establish normal values for range of motion (ROM) of the vertebral column in a uniform population of horses trotting under different conditions. STUDY DESIGN: Vertebral ROM was established in Franches-Montagnes stallions and a general population of horses and the variability in measurements compared between the two groups. Repeatability and the influence of specific exercise condition (on ROM) were assessed. Finally, attempts were made to explain the findings of the study through the evaluation of factors that might influence ROM. METHODS: Dorsoventral (DV) and mediolateral (ML) vertebral ROM was measured at a trot under different exercise conditions in 27 Franches-Montagnes stallions and six general population horses using IMUs distributed over the vertebral column. RESULTS: Variability in the ROM measurements was significantly higher for general population horses than for Franches-Montagnes stallions (both DV and ML ROM). Repeatability was strong to very strong for DV measurements and moderate for ML measurements. Trotting under saddle significantly reduced the ROM, with sitting trot resulting in a significantly lower ROM than rising trot. Age is unlikely to explain the low variability in vertebral ROM recorded in the Franches-Montagnes horses, while this may be associated with conformational factors. CONCLUSIONS: It was possible to establish a normal vertebral ROM for a group of Franches-Montagnes stallions. While within-breed variation was low in this population, further studies are necessary to determine variation in vertebral ROM for other breeds and to assess their utility for diagnosis of equine back disorders.

Analytical, physiologic, and clinical validation of a radioimmunoassay for measurement of procollagen type III amino terminal propeptide in serum and bronchoalveolar lavage fluid obtained from dogs.

OBJECTIVE To validate a radioimmunoassay for measurement of procollagen type III amino terminal propeptide (PIIINP) concentrations in canine serum and bronchoalveolar lavage fluid (BALF) and investigate the effects of physiologic and pathologic conditions on PIIINP concentrations. SAMPLE POPULATION Sera from healthy adult (n = 70) and growing dogs (20) and dogs with chronic renal failure (CRF; 10), cardiomyopathy (CMP; 12), or degenerative valve disease (DVD; 26); and sera and BALF from dogs with chronic bronchopneumopathy (CBP; 15) and healthy control dogs (10 growing and 9 adult dogs). PROCEDURE A radioimmunoassay was validated, and a reference range for serum PIIINP (S-PIIINP) concentration was established. Effects of growth, age, sex, weight, CRF, and heart failure on S-PIIINP concentration were analyzed. In CBP-affected dogs, S-PIIINP and BALF-PIIINP concentrations were evaluated. RESULTS The radioimmunoassay had good sensitivity, linearity, precision, and reproducibility and reasonable accuracy for measurement of S-PIIINP and BALF-PIIINP concentrations. The S-PIIINP concentration reference range in adult dogs was 8.86 to 11.48 mug/L. Serum PIIINP concentration correlated with weight and age. Growing dogs had significantly higher S-PIIINP concentrations than adults, but concentrations in CRF-, CMP-, DVD-, or CBP-affected dogs were not significantly different from control values. Mean BALF-PIIINP concentration was significantly higher in CBP-affected dogs than in healthy adults. CONCLUSIONS AND CLINICAL RELEVANCE In dogs, renal or cardiac disease or CBP did not significantly affect S-PIIINP concentration; dogs with CBP had high BALF-PIIINP concentrations. Data suggest that the use of PIIINP as a marker of pathologic fibrosis might be limited in growing dogs.

Clinical acid-base pathophysiology: disorders of plasma anion gap.

The plasma anion gap is a frequently used parameter in the clinical diagnosis of a variety of conditions. The commonest application of the anion gap is to classify cases of metabolic acidosis into those that do and those that do not leave unmeasured anions in the plasma. While this algorithm is useful in streamlining the diagnostic process, it should not be used solely in this fashion. The anion gap measures the difference between the unmeasured anions and unmeasured cations and thus conveys much more information to the clinician than just quantifying anions of strong acids. In this chapter, the significance of the anion gap is emphasized and several examples are given to illustrate a more analytic approach to using the clinical anion gap; these include disorders of low anion gap, respiratory alkalosis and pyroglutamic acidosis.

Trends of periodontal conditions in two different randomly selected Swiss (Bernese) cohorts 25 years apart

AIM To assess the periodontal conditions of two randomly selected Swiss cohorts 25 years apart. MATERIAL AND METHODS Standardized examinations were performed to assess the periodontal conditions of two randomly selected populations of the Canton of Bern; oral cleanliness was evaluated using the plaque index (PlI) and the retention index (RI). Gingival health was scored according to the gingival index (GI). Periodontal conditions were evaluated by pocket probing depth (PPD) and loss of attachment (LA). RESULTS At the first examination in 1985, 206 out of 350 subjects were evaluated, while in the second examination in 2010, 134 out of 490 subjects attended the examinations. In 1985, subjects showed a mean PlI of 1.16, and 0.77 in 2010. RI was 0.81 and 0.36 in 1985 and 2010 respectively. Mean GI was 1.34 and 0.6. The mean proportion of PPD ≤3 mm was 72% in 1985 and 97.3% in 2010. PPD ≥ 6 mm affected 2.0% in 1985 and 0.3% in 2010. In 1985, subjects had an average of 20.7 teeth, while in 2010, the average was 24.6. In 1985, 7.3% of the subjects were edentulous, while in 2010, 4.5% had no teeth. CONCLUSIONS Trends to improvements resulting in more teeth in function and better periodontal conditions were recognized.

Immediate implant placement with simultaneous guided bone regeneration in the esthetic zone: 10-year clinical and radiographic outcomes.

AIM To associate the dimension of the facial bone wall with clinical, radiological, and patient-centered outcomes at least 10 years after immediate implant placement with simultaneous guided bone regeneration in a retrospective study. MATERIAL AND METHODS Primary endpoint was the distance from the implant shoulder (IS) to the first bone-to-implant contact (IS-BIC10y ). Secondary endpoints included the facial bone thickness (BT10y ) 2, 4, and 6 mm apical to the IS, and the implant position. At baseline, the horizontal defect width (HDWBL ) from the implant surface to the alveolar wall was recorded. At recall, distance from the IS to the mucosal margin (IS-MM10y ), degree of soft tissue coverage of the mesial and distal aspects of the implants (PISm10y , PISd10y ; Papilla Index), pocket probing depth (PPD10y ), and patient-centered outcomes were determined. Width of the keratinized mucosa (KM), Full-Mouth Plaque and Bleeding Score (FMPS, FMBS) were available for both time points. RESULTS Of the 20 patients who underwent immediate implant placement with simultaneous guided bone regeneration and transmucosal healing, nine males and eight females with a median age of 62 years (42 min, 84 max) were followed up for a median period of 10.5 y (min 10.1 max 11.5). The 10-year implant survival rate was 100%. Multivariate regression analysis revealed a correlation of the IS-BIC10y , controlled for age and gender, with four parameters: HDWBL (P = 0.03), KMBL -10 (P = 0.02), BT10 4 mm (P = 0.01), and BT10 6 mm (P = 0.01). CONCLUSION Within the conditions of the present study, the horizontal defect width was the main indicator for the vertical dimension of the facial bone. The facial bone dimension was further associated with a reduction in the width of the keratinized mucosa and the dimension of the buccal bone.

Accuracy of continuous glucose monitoring during differing exercise conditions.

AIM Depending on intensity, exercise may induce a strong hormonal and metabolic response, including acid-base imbalances and changes in microcirculation, potentially interfering with the accuracy of continuous glucose monitoring (CGM). The present study aimed at comparing the accuracy of the Dexcom G4 Platinum (DG4P) CGM during continuous moderate and intermittent high-intensity exercise (IHE) in adults with type 1 diabetes (T1DM). METHODS Ten male individuals with well-controlled T1DM (HbA1c 7.0±0.6% [54±6mmol/mol]) inserted the DG4P sensor 2 days prior to a 90min cycling session (50% VO2peak) either with (IHE) or without (CONT) a 10s all-out sprint every 10min. Venous blood samples for reference glucose measurement were drawn every 10min and euglycemia (target 7mmol/l) was maintained using an oral glucose solution. Additionally, lactate and venous blood gas variables were determined. RESULTS Mean reference blood glucose was 7.6±0.2mmol/l during IHE and 6.7±0.2mmol/l during CONT (p<0.001). IHE resulted in significantly higher levels of lactate (7.3±0.5mmol/l vs. 2.6±0.3mmol/l, p<0.001), while pH values were significantly lower in the IHE group (7.27 vs. 7.38, p=0.001). Mean absolute relative difference (MARD) was 13.3±2.2% for IHE and 13.6±2.8% for CONT suggesting comparable accuracy (p=0.90). Using Clarke Error Grid Analysis, 100% of CGM values during both IHE and CONT were in zones A and B (IHE: 77% and 23%; CONT: 78% and 22%). CONCLUSIONS The present study revealed good and comparable accuracy of the DG4P CGM system during intermittent high intensity and continuous moderate intensity exercise, despite marked differences in metabolic conditions. This corroborates the clinical robustness of CGM under differing exercise conditions. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT02068638.

Antimicrobial drug use and risk factors associated with treatment incidence and mortality in Swiss veal calves reared under improved welfare conditions

Ninety-one Swiss veal farms producing under a label with improved welfare standards were visited between August and December 2014 to investigate risk factors related to antimicrobial drug use and mortality. All herds consisted of own and purchased calves, with a median of 77.4% of purchased calves. The calves' mean age was 29±15days at purchasing and the fattening period lasted at average 120±28 days. The mean carcass weight was 125±12kg. A mean of 58±33 calves were fattened per farm and year, and purchased calves were bought from a mean of 20±17 farms of origin. Antimicrobial drug treatment incidence was calculated with the defined daily dose methodology. The mean treatment incidence (TIADD) was 21±15 daily doses per calf and year. The mean mortality risk was 4.1%, calves died at a mean age of 94±50 days, and the main causes of death were bovine respiratory disease (BRD, 50%) and gastro-intestinal disease (33%). Two multivariable models were constructed, for antimicrobial drug treatment incidence (53 farms) and mortality (91 farms). No quarantine, shared air space for several groups of calves, and no clinical examination upon arrival at the farm were associated with increased antimicrobial treatment incidence. Maximum group size and weight differences >100kg within a group were associated with increased mortality risk, while vaccination and beef breed were associated with decreased mortality risk. The majority of antimicrobial treatments (84.6%) were given as group treatments with oral powder fed through an automatic milk feeding system. Combination products containing chlortetracycline with tylosin and sulfadimidine or with spiramycin were used for 54.9%, and amoxicillin for 43.7% of the oral group treatments. The main indication for individual treatment was BRD (73%). The mean age at the time of treatment was 51 days, corresponding to an estimated weight of 80-100kg. Individual treatments were mainly applied through injections (88.5%), and included administration of fluoroquinolones in 38.3%, penicillines (amoxicillin or benzylpenicillin) in 25.6%, macrolides in 13.1%, tetracyclines in 12.0%, 3th and 4th generation cephalosporines in 4.7%, and florfenicol in 3.9% of the cases. The present study allowed for identifying risk factors for increased antimicrobial drug treatment and mortality. This is an important basis for future studies aiming at reducing treatment incidence and mortality in veal farms. Our results indicate that improvement is needed in the selection of drugs for the treatment of veal calves according to the principles of prudent use of antibiotics.