Study protocol for OptimalTTF-2: enhancing Tumor Treating Fields with skull remodeling surgery for first recurrence glioblastoma: a phase 2, multi-center, randomized, prospective, interventional trial.

BACKGROUND: OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional study aiming to test skull remodeling surgery in combination with Tumor Treating Fields therapy (TTFields) and best physicians choice medical oncological therapy for first recurrence in glioblastoma patients. OptimalTTF-2 is a phase 2 trial initiated in November 2020. Skull remodeling surgery consists of five burrholes, each 15 mm in diameter, directly over the tumor resection cavity. Preclinical research indicates that this procedure enhances the effect of Tumor Treating Fields considerably. We recently concluded a phase 1 safety/feasibility trial that indicated improved overall survival and no additional toxicity. This phase 2 trial aims to validate the efficacy of the proposed intervention. METHODS: The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients, an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields therapy combined with best physicians choice oncological treatment (control arm) or b) skull remodeling surgery, TTFields therapy and best practice oncology (interventional arm). Major eligibility criteria include age ≥ 18 years, 1st recurrence of supratentorial glioblastoma, Karnofsky performance score ≥ 70, focal tumor, and lack of significant co-morbidity. Study design aims to detect a 20% increase in overall survival after 12 months (OS12), assuming OS12 = 40% in the control group and OS12 = 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective tumor response rate, quality of life, KPS, steroid dose, and toxicity. Toxicity, objective tumor response rate, and QoL will be assessed every 3rd month. Endpoint data will be collected at the end of the trial, including the occurrence of suspected unexpected serious adverse reactions (SUSARs), unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up. DISCUSSION: New treatment modalities are highly needed for first recurrence glioblastoma. Our proposed treatment modality of skull remodeling surgery, Tumor Treating Fields, and best practice medical oncological therapy may increase overall survival significantly. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0422399 , registered 13. January 2020.

Monitoring meticillin resistant Staphylococcus aureus and its spread in Copenhagen, Denmark, 2013, through routine whole genome sequencing.

Typing of meticillin resistant Staphylococcus aureus (MRSA) by whole genome sequencing (WGS) is performed routinely in Copenhagen since January 2013. We describe the relatedness, based on WGS data and epidemiological data, of 341 MRSA isolates. These comprised all MRSA (n = 300) identified in Copenhagen in the first five months of 2013. Moreover, because MRSA of staphylococcal protein A (spa)-type 304 (t304), sequence type (ST) 6 had been associated with a continuous neonatal ward outbreak in Copenhagen starting in 2011, 41 t304 isolates collected in the city between 2010 and 2012 were also included. Isolates from 2013 found to be of t304, ST6 (n=14) were compared to the 41 earlier isolates. In the study, isolates of clonal complex (CC) 22 were examined in detail, as this CC has been shown to include the hospital-acquired epidemic MRSA (EMRSA-15) clone. Finally, all MRSA ST80 were also further analysed, as representatives of an important community-acquired MRSA in Europe. Overall the analysis identified 85 spa-types and 35 STs from 17 CCs. WGS confirmed the relatedness of epidemiologically linked t304 neonatal outbreak isolates. Several non-outbreak related patients had isolates closely related to the neonatal isolates suggesting unrecognised community chains of transmission and insufficient epidemiological data. Only four CC22 isolates were related to EMRSA-15. No community spread was observed among the 13 ST80 isolates. WGS successfully replaced conventional typing and added information to epidemiological surveillance. Creation of a MRSA database allows clustering of isolates based on single nucleotide polymorphism (SNP) calling and has improved our understanding of MRSA transmission.

Rise and subsequent decline of community-associated methicillin resistant Staphylococcus aureus ST30-IVc in Copenhagen, Denmark through an effective search and destroy policy.

The number of patients with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has increased rapidly in Copenhagen, Denmark since 2003. Patients with the typical Panton-Valentine leukocidin-positive CA-MRSA clone ST30-IVc were contacted with the aim of treating MRSA carriers, evaluating the effect of MRSA eradication therapy (ET), and finding links among patients. Twenty-three index patients infected with the ST30-IVc clone from November 2003 to September 2005 were contacted and transmission chains were studied. The majority of ST30-IVc patients had a connection to the Philippines. Household members were screened for MRSA and all members of families with MRSA carriers were offered treatment of the carrier state and were followed for 1 year. MRSA carriers were found in seven of 16 households and transmission occurred among close contacts and in kindergartens. Five days of ET was insufficient and at least one person in each household was treated with systemic antibiotics. All families were MRSA negative at 1-year follow-up. The CA-MRSA clone ST30-IVc has been imported to Copenhagen, Denmark, primarily from the Philippines, and has spread through close contacts and in kindergartens. Treatment of MRSA carriers was difficult and required many resources, but the clone was eventually successfully eliminated. The import of ST30-IVc to Denmark will continue, but the spread of the clone in Denmark can be kept to a minimum by direct intervention in the affected families.

Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single procalcitonin measurement at hospital admission--a randomized trial.

Recent studies have suggested that procalcitonin (PCT) is a safe marker for the discrimination between bacterial and viral infection, and that PCT-guided treatment may lead to substantial reductions in antibiotic use. The present objective was to evaluate the effect of a single PCT measurement on antibiotic use in suspected lower respiratory tract infections (LRTIs) in a Danish hospital setting. In a randomized, controlled intervention study, 223 adult patients admitted to the hospital because of suspicion of LRTI were included with 210 patients available for analysis. Patients were randomized to either PCT-guided treatment or standard treatment. Antibiotic treatment duration in the PCT group was based on the serum PCT value at admission. The cut-off point for recommending antibiotic treatment was PCT > or =0.25 microg/L. Physicians could overrule treatment guidelines. The mean duration of hospital stay was 5.9 days in the PCT group vs. 6.7 days in the control group (p 0.22). The mean duration of antibiotic treatment during hospitalization in the PCT group was 5.1 days on average, as compared to 6.8 days in the control group (p 0.007). In a subgroup analysis of chronic obstructive pulmonary disease patients, the mean length of stay was reduced from 7.1 days in the control group to 4.8 days in the PCT group (p 0.009). It was concluded that the determination of a single PCT value at admission in patients with suspected LRTIs can lead to a reduction in the duration of antibiotic treatment by 25% without compromising outcome. No effect on the length of hospital stay was found.

Environmental meticillin-resistant Staphylococcus aureus (MRSA) disinfection using dry-mist-generated hydrogen peroxide.

Meticillin-resistant Staphylococcus aureus (MRSA) is a major problem in hospitals worldwide. Hand hygiene is recognised as crucial in limiting the spread of MRSA but less is known about the role of MRSA reservoirs in the inanimate hospital environment. We evaluated the effect of hydrogen peroxide vapour diffused by Sterinis((R)) against MRSA in two experimental hospital settings and in two field trials. Dipslides were used for MRSA detection and quantification before and after using the Sterinis disinfection process. In the first experimental hospital setting, four epidemic MRSA strains were placed at five locations and left for one week. All strains survived the week but not the disinfection process. In field trial one 14 upholstered chairs from a department with many MRSA positive patients were left for one month in a closed room prior to disinfection. MRSA was found on the upholstery of four of the 14 chairs. Three chairs became MRSA negative immediately after the disinfection, the fourth 24h later. The second field trial was in the private home of a MRSA positive family of four individuals. One location was found MRSA positive, remaining so after the Sterinis cycles. We found Sterinis to be effective against MRSA in the experimental hospital setting and upholstered chairs, but not in the private home of heavily colonised MRSA patients.

Pediatric pancreatic trauma: predictors of nonoperative management failure and associated outcomes.

BACKGROUND: Nonoperative management (NOM) is an accepted treatment of pediatric solid organ injuries and is typically successful. Blunt pancreatic trauma tends to require operative intervention more frequently. We sought to identify predictors of failure of NOM and compare the outcome of operative management against NOM. METHODS: A retrospective analysis was performed from January 1993 to December 2002 of all children with blunt pancreatic injuries from the trauma registries of 7 designated level 1 pediatric trauma centers. Failure of NOM was defined as the need for intraabdominal operative intervention. Injuries were graded I to V, and ductal injury was defined as grades III to V. Parameters included mechanism of injury, injury severity score (ISS), organ grade, Glasgow Coma Scale score, and outcome. Data were analyzed by Fisher exact test and Mann-Whitney U test, with mean values +/- SD and significance of P < .05. RESULTS: Pancreatic injuries were present in 173 (9.2%) of 1823 patients. Of these, 43 (26.0% [43/173]) required an operation. Valid morbidity data was obtained in 118 of 173 patients. ISS was significantly higher in all patients treated operatively. Patients with an injury of grade III to V failed NOM more frequently than all patients with pancreatic injury (P =.0169). Length of stay was longer, and the incidence of pseudocysts, drainage procedures, and pancreatitis was higher in NOM patients, although not significant. CONCLUSIONS: Patients with pancreatic injuries had a NOM failure rate of 26.0%. ISS and injury grades III to V were predictors of NOM failure. Patients with pancreatic ductal injury require more aggressive management.

Towards a theory of interrupted feelings.

The purpose of this study is to identify central aspects of feelings in relation to the experience of being a brother or sister of someone who suffers from schizophrenia. The study makes use of a hermeneutical method for the collection of data as well as for the systemizing and interpretation of data. The participants in the study were 16 siblings of persons with diagnosed schizophrenia. In total 80 interviews were done, with an average length of 50 min. A theory of interrupted feelings was developed within the tension between empirical data and preunderstanding. Mixed feelings of grief, hope, anger, guilt and shame are interrupted by four interrelated factors: ambiguous loss, the fluctuating nature of the illness, an inner prohibition of feelings and the tendency of others to invalidate the feelings. The interruption may lead to a lonely and painful experience which is difficult both to process for oneself and to share with others.

The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part I.

OBJECTIVE: To determine whether a supplement of folic acid given preconceptionally or early in pregnancy had any influence on, birth weight, incidence of preterm labour, low birth weight and small for gestational age. Furthermore, the aim was to elucidate, whether the outcome differed following the administration of two different dosages of folic acid, namely 2.5 and 1.0 mg. MATERIAL: All women in the childbearing age living on the island of Funen, Denmark (population 500,000) were offered a supplement of folic acid over a period of 3 years and 3 months. 14,021 women, who gave birth to 13,860 single-born and 325 multiborn children, were registered. A total of 8184 women took part in the double-blind randomized trial: 2310 had a supplement of folic acid without being randomized and 2721 women received no folic acid supplement. No information regarding the use of folic acid was available in 806 pregnancies. Abortions (512) were excluded. RESULTS AND CONCLUSIONS: A supplement 1.0 mg folic acid had the same effect as 2.5 mg. The effects of supplementing the diet with folic acid given preconceptionally or in the first half of pregnancy in an affluent Northern country were a slight increase of birth weight and a decrease in the incidence of preterm labour, infants with low birth weight and small for gestational age. The greatest effect was seen in the groups receiving folic acid preconceptionally.

The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part III. Congenital anomalies. An observational study.

OBJECTIVE: The effect of folic acid supplement on the prevalence of congenital anomalies was studied in a Danish population. MATERIAL AND METHODS: From 1983 to 1986 all Danish women resident in the county of Funen were offered free folic acid when pregnant or planning a pregnancy. Data concerning the starting time of folic acid supplement and congenital anomalies were recorded on close to all pregnancies. Children of folic acid supplemented mothers were subdivided as to start of supplement with dividing lines at week 7 and week 11 calculated from the last menstrual period. Structural malformations were subdivided into an early group with malformation development in the first 7 weeks from the last menstrual period and a late group where malformations develop in weeks 8 to 11. RESULTS: In a total of 14,021 pregnancies 10,494 pregnant women (74.8%) had folic acid supplement. No folic acid was taken by 2721 women (19.4%) and in 806 cases (5.8%) information was lacking. The prevalence of congenital anomalies was 380 in 14,185 children (26.7/1000). Children whose mothers started folic acid supplement before the 7th week of pregnancy showed a significantly lower prevalence of the malformations which develop in the first 7 weeks, when compared to pregnancies with a later start of supplement. The result was interpreted as a clearcut trend.

The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part II. Congenital anomalies. A randomised study.

OBJECTIVE: The effect of folic acid supplement on the prevalence of congenital anomalies was studied in a Danish population. MATERIAL AND METHODS: From 1983 to 1986 all Danish women resident in the county of Funen were offered free folic acid when pregnant or planning a pregnancy. Folic acid dose was randomised to 2.5 or 1.0 mg. A randomised control group was not feasible for ethical reasons. Hospitals, midwives and most general practitioners cooperated to procure information on close to all pregnancies and congenital anomalies were recorded. RESULTS AND CONCLUSIONS: In a total of 14,021 pregnancies resulting in child birth 8184 women (58.4%) had folic acid with randomisation. Supplement was started in the randomised group before the last menstrual period in 1359/8184 (16.6%) and in the first 19 weeks of pregnancy in 6825/8184 (83.4%). The prevalence of congenital anomalies was 224 in 8293 children (27.0/1000). No dose-dependent differences were found in either total anomalies or in those specific malformations which have been reported to occur with reduced prevalence with periconceptional folic acid. The result was probably influenced by a start of supplement too late to affect malformation development in many cases and by the high level of both folic acid doses given compared to usual recommendations. Pregnancies without folic acid supplement showed prevalences similar to the supplemented groups.

[Air quality and microbiologic contamination in operating theatres]. / Luftkvalitet og mikrobiologisk kontaminering i operasjonsstuer.

The present study concerns the air quality and microbiological contamination in two newly built operating theatres; one with laminar air flow (LAF) equipment for cardio-thoracic operations, and one with conventional ventilation for urological operations. Both theatres had an identical number of air exchanges (17/h), identical microclimatic conditions and they employed the same cleaning procedures. In the LAF-ventilated operating theatre bacterial contamination of the air was effectively reduced to less than 10 colony-forming units (CFU)/m3 in all 125 samples (1 m3 per sample) tested. In most samples, 118/125, the bacterial count was less than 5 CFU/m3, despite the presence of ten persons. The conventionally ventilated theatre reached values up to 120 CFU/m3 during the most active period of the day when approximately seven persons were present. The LAF ventilation reduced both the content of particles in the air and contamination by bacteria on the floor. In both theatres cleaning procedures had only a low impact on CFU in the air and on the floor. The use of diathermia markedly increased the level of small particles in the air, and this may influence the air quality in the operating theatres.

[Use of natural medicines in women referred to specialists]. / Brug af naturmedicin hos kvinder henvist til speciallaege.

The aim was to examine how often women referred to office gynaecologists were using self-medication of "natural medicines". By interview-questionnaires 62 gynaecologists asked 5.664 women about their age, name of used natural medicine and how the user felt it helped her. One thousand six hundred and sixty-four used natural medicine with 91 different names. About 75% percent of the users registered one or more effects, characterized as "good for everything", "enhances their wellbeing" "gives more energy", "relieves hot flushes and sweatings", "relieves rheumatic pain", or "is diuretic". The effects seem to be a universal stimulation of the general condition, effectuated either by vitamins and minerals or by placebo-effect. One third of the users of "melbrosia" registered a good effect on climacteric discomfort. It was not possible by laboratory analyses to find any sex-steroids in melbrosia. Nor was it possible to demonstrate biological oestrogenic effect on animals (mice and rats) of this drug in a trial done by Niels Einer-Jensen et al (personal communication).

Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats.

OBJECTIVES: The natural medicines, Cimicifuga and Melbrosia, are widely sold. Cimicifuga is an extract of Cimicifuga racemosa (L.), and Melbrosia is a mixture of Gelée Royale, perga-pollen and pollen. Cimicifuga and Melbrosia are used through self-medication to relieve symptoms of hot flushes and other menstrual or menopausal discomfort in many of the Danish women consulting private gynaecologists. A gynaecologist tends to treat these symptoms with oestrogen, so the present experiments were therefore made to investigate whether Cimicifuga and Melbrosia have oestrogenic effects as defined by the classical biological methods: uterine growth in immature mice and vaginal cornification in ovariectomized rats. METHODS: Vehicle, 6, 60 or 600 mg/kg Cimicifuga or 30, 300 or 3000 mg/kg Melbrosia was administered orally for 3 days to groups of 10 immature mice and the uterus weight measured on the fourth day. Similarly, vehicle, 6, 60, 600 mg/kg Cimicifuga or 3, 30, 300 mg/kg Melbrosia was injected subcutaneously in groups of 12 ovariectomized rats for 3 days and vaginal smears investigated for signs of cornified cells. All experiments were repeated once. RESULTS: No signs of an oestrogenic effect connected with the preparations were found in any of the experiments. CONCLUSIONS: It can be concluded that the eventual beneficial effects on menstrual or menopausal discomfort connected with Cimicifuga and Melbrosia self-medication cannot be explained as a traditional oestrogenic effect as measured in biological experiments.

Staphylococcus aureus carriage and infections among patients in four haemo- and peritoneal-dialysis centres in Denmark. The Danish Study Group of Peritonitis in Dialysis (DASPID).

A three-month prospective surveillance study was undertaken in four dialysis centres to establish the prevalence of Staphylococcus aureus carriage in a Danish population of patients on haemodialysis (HD) or on continuous ambulatory peritoneal dialysis (CAPD). General data such as sex, age, diagnosis, number of months in dialysis, hospital and ward were registered on a precoded form. Standardized nose and four skin swabs (axillae, groins, perineum) were performed on the first day of the survey. After one and two months, nose swabs were collected. Infections were registered and cultures were sent for phage-typing together with the S. aureus strains isolated from the swabs; 59.5% of HD patients and 51.2% of CAPD patients carried S. aureus. Permanent carriage was most frequent (P < 0.00009), primarily in the nose (44.0 and 34.9%, respectively in HD and CAPD). Skin carriage alone was rare (2.4 and 4.7%). Approximately one third (36.6 and 40.7%) of infections were caused by S. aureus. Although diabetics were not significantly more frequent carriers (60.5%) than non-diabetics (55.0%), the incidence of infection was much higher (26.3% vs. 10.3%, P = 0.004). In CAPD, peritonitis and tunnel/exit-site infections predominated (81.4%), often caused by S. aureus (34.8%). More than two thirds of the infections in HD patients were related to intravascular catheterization. The most serious infection was septicaemia, in all cases due to S. aureus. S aureus infections occurred significantly more frequently among carriers (P = 0.005), and more than half the patients were infected by the same or possibly the same strain as they carried in the nose or on skin. Different regimens for the elimination of S. aureus carriage in dialysis patients are discussed. A policy for risk assessment of patients should be developed, and the elimination of S. aureus carriage before dialysis should be encouraged. Controlled trials comparing the cost-effectiveness of recommended regimens to eliminate carriage in HD/CAPD patients are needed. Nose swabs are reliable indicators of carriage in dialysis patients.

Predictive analog to digital conversion of Doppler ultrasound signals.

Analog to digital conversion in multigate Doppler ultrasound systems for blood velocity measurements is a technological challenge. The echoes must be digitized at a rate determined by the system bandwidth (typically 2 MHz), and the dynamic range is large (16 bits or more) due to the presence of strong, low-frequency Doppler clutter echoes originating from slowly moving tissue. Off-the-shelf A/D converters do not meet these requirements with the transducer configuration employed by contemporary Doppler systems. Analysis reveals a 5-b reduction in required wordlength for an A/D converter in a predictive feedback loop when the maximum clutter frequency is about 1.5% of the pulse repetition frequency. The prediction error filter is recursive. Alternatively, first- and second-order DPCM (Differential Pulse Code Modulation) yield 4 and 6 b, respectively. With short input segments (from a high-resolution Color Flow Mapper), the results are, in the above order, 4, 4, and 5 b. The results are verified by processing an experimental Doppler signal.

Velocity matched spectrum analysis: a new method for suppressing velocity ambiguity in pulsed-wave Doppler.

A new approach to spectrum analysis, which is capable of suppressing velocity ambiguity in pulsed-wave ultrasonic Doppler, is presented. By simultaneous processing of several data samples from a range in depth, the movement of the scatterers along the ultrasonic beam can be tracked from pulse to pulse for each velocity component in the spectrum. In this way the correlation length of the signal component arising from a specific velocity increases when that velocity matches the expected velocity. The resulting velocity/time spectral display shows a more clearly defined spectral envelope of the maximum velocity than with conventional methods based on the discrete Fourier transform of the Doppler signal. This makes it possible to delineate velocity waveforms with peak velocity up to several times the Nyquist limit. Experimental data from human subclavian and aortic arteries are presented, where the new method is compared to conventional spectrum analysis.

Pseudo-outbreak of pseudomonas aeruginosa in HIV-infected patients undergoing fiberoptic bronchoscopy.

Pseudomonas aeruginosa was isolated from bronchoalveolar lavage fluid from 8 consecutive patients undergoing bronchoscopy at an infectious diseases unit. None of the patients developed signs of respiratory tract infection that could be ascribed to the organism. The source of contamination was the suction channels of 2 fiberoptic bronchoscopes which, due to a lapse in routine procedures, were not cleansed manually prior to disinfection with glutaraldehyde. Although rarely of pathogenetic importance, the possible presence of P. aeruginosa in lavage fluids should never be discounted, as it may indicate faulty disinfection of bronchoscopy equipment and thereby point to a risk of transmission of true respiratory pathogens such as mycobacteria.

Outbreak of infection in a burns unit due to Pseudomonas aeruginosa originating from contaminated tubing used for irrigation of patients.

Five patients with extensive deep burns developed septicaemia due to Pseudomonas aeruginosa serogroup O-7.8 and phage type 21 or 21/188 shortly after they had been admitted to hospital. Four other burned patients became colonized with the same strain. The source of infection was contaminated tap water used for irrigation of the burns, as part of the first-aid treatment which the patients received when entering the hospital. Contamination was restricted to showers and tubing that were permanently connected to the taps, and the outbreak stopped after they had been disinfected. Tubing and showers used for irrigation of burns should be dismantled and heat-disinfected after each patient and not reconnected to the taps until immediately before the next treatment. Taps used for irrigation of burns should be monitored regularly for the presence of P. aeruginosa and other potentially pathogenic bacteria. Routine typing of P. aeruginosa isolates from burned patients is indicated in order to detect and eliminate hidden sources of infection.