Vancouver call for action to strengthen expertise in radiological protection worldwide.

Ionising radiation has been used for over a century for peaceful purposes, revolutionising health care and promoting well-being through its application in industry, science, and medicine. For almost as long, the International Commission on Radiological Protection (ICRP) has promoted understanding of health and environmental risks of ionising radiation and developed a protection system that enables the safe use of ionising radiation in justified and beneficial practices, providing protection from all sources of radiation. However, we are concerned that a shortage of investment in training, education, research, and infrastructure seen in many sectors and countries may compromise society's ability to properly manage radiation risks, leading to unjustified exposure to or unwarranted fear of radiation, impacting the physical, mental, and social well-being of our peoples. This could unduly limit the potential for research and development in new radiation technologies (healthcare, energy, and the environment) for beneficial purposes. ICRP therefore calls for action to strengthen expertise in radiological protection worldwide through: (1) National governments and funding agencies strengthening resources for radiological protection research allocated by governments and international organisations, (2) National research laboratories and other institutions launching and sustaining long-term research programmes, (3) Universities developing undergraduate and graduate university programmes and making students aware of job opportunities in radiation-related fields, (4) Using plain language when interacting with the public and decision makers about radiological protection, and (5) Fostering general awareness of proper uses of radiation and radiological protection through education and training of information multipliers. The draft call was discussed with international organisations in formal relations with ICRP in October 2022 at the European Radiation Protection Week in Estoril, Portugal, and the final call announced at the 6th International Symposium on the System of Radiological Protection of ICRP in November 2022 in Vancouver, Canada.

Keeping the ICRP recommendations fit for purpose.

The International Commission on Radiological Protection (ICRP) has embarked on a review and revision of the system of Radiological Protection that will update the 2007 general recommendations in ICRPPublication 103. This is the beginning of a process that will take several years, involving open and transparent engagement with organisations and individuals around the world. While the system is robust and has performed well, it must adapt to address changes in science and society to remain fit for purpose. The aim of this paper is to encourage discussions on which areas of the system might gain the greatest benefit from review, and to initiate collaborative efforts. Increased clarity and consistency are high priorities. The better the system is understood, the more effectively it can be applied, resulting in improved protection and increased harmonisation. Many areas are identified for potential review including: classification of effects, with particular focus on tissue reactions; reformulation of detriment, potentially including non-cancer diseases; re-evaluation of the relationship between detriment and effective dose, and the possibility of defining detriments for males and females of different ages; individual variation in the response to radiation exposure; heritable effects; and effects and risks in non-human biota and ecosystems. Some of the basic concepts are also being considered, including the framework for bringing together protection of people and the environment, incremental improvements to the fundamental principles of justification and optimisation, a broader approach to protection of individuals, and clarification of the exposure situations introduced in 2007. In addition, ICRP is considering identifying where explicit incorporation of the ethical basis of the system would be beneficial, how to better reflect the importance of communications and stakeholder involvement, and further advice on education and training. ICRP invites responses on these and other areas relating to the review of the System of Radiological Protection.

Possibilities and challenges in developing and implementing an empowerment-based school-intervention in a Swedish disadvantaged community.

In this paper, we describe and critically reflect on the possibilities and challenges of developing and implementing an empowerment-based school intervention regarding healthy food and physical activity (PA), involving participants from a Swedish multicultural area characterized by low socioeconomic status. The 2-year intervention was continually developed and implemented, as a result of cooperation and shared decision making among researchers and the participants. All 54 participants were seventh graders, and the intervention comprised health coaching, health promotion sessions and a Facebook group. We experienced that participants valued collaborating with peers, and that they took responsibility in codeveloping and implementing the intervention. Participants expressed feeling listened to, being treated with respect and taken seriously. However, we also experienced a number of barriers that challenged our initial intentions of aiding participation and ambition to support empowerment. Moreover, it was challenging to use structured group health coaching and to work with goal-setting in groups of participants with shared, and sometimes competing, goals, wishes and needs related to food and PA. Successful experiences from this intervention was the importance of acquiring a broad and deep understanding of the context and participants, being open to negotiating, as well as adjusting the intervention.

The Influence of Different Designs, Materials and Cements on the Success and Survival Rate of Endocrowns. A Systematic Review.

The aim is to evaluate the success and survival rate of endocrowns and the influence of design, material and cements. A search of clinical trials of endocrowns was performed using three databases (Medline/PubMed, Scopus, CochraneLibrary), complemented by a manual search. The search resulted in 2,718 studies, six of which were included for analysis. The follow-up times were 2-12 years. Feldspathic porcelain was the material of choice cemented with different adhesive resin cement systems. Designs varied significantly. In total, the six studies represented 471 endocrowns. Thirty-six of these failed. Most common failures were loss of retention and fracture. Due to insufficient information on timing of events and drop-out, no statistical analysis was performed. No conclusive correlation between design, material, cement and success or survival of endocrowns could be established. Signs of differences in survival rates between molar and premolar endocrowns were noted, with a tendency towards higher survival rates for molar endocrowns. Feldspathic ceramic endocrowns with adhesive cementation demonstrate promising clinical performance. These conclusions are however based on a limited number of studies of comparatively low quality. Further studies are thus needed to verify the conclusions and to provide guidance in the clinical decision on best choice of materials, design and cements.

Minimizing inequality in access to precision medicine in breast cancer by real-time population-based molecular analysis in the SCAN-B initiative.

BACKGROUND: Selection of systemic therapy for primary breast cancer is currently based on clinical biomarkers along with stage. Novel genomic tests are continuously being introduced as more precise tools for guidance of therapy, although they are often developed for specific patient subgroups. The Sweden Cancerome Analysis Network - Breast (SCAN-B) initiative aims to include all patients with breast cancer for tumour genomic analysis, and to deliver molecular subtype and mutational data back to the treating physician. METHODS: An infrastructure for collection of blood and fresh tumour tissue from all patients newly diagnosed with breast cancer was set up in 2010, initially including seven hospitals within the southern Sweden regional catchment area, which has 1.8 million inhabitants. Inclusion of patients was implemented into routine clinical care, with collection of tumour tissue at local pathology departments for transport to the central laboratory, where routines for rapid sample processing, RNA sequencing and biomarker reporting were developed. RESULTS: More than 10 000 patients from nine hospitals have currently consented to inclusion in SCAN-B with high (90 per cent) inclusion rates from both university and secondary hospitals. Tumour samples and successful RNA sequencing are being obtained from more than 70 per cent of patients, showing excellent representation compared with the national quality registry as a truly population-based cohort. Molecular biomarker reports can be delivered to multidisciplinary conferences within 1 week. CONCLUSION: Population-based collection of fresh tumour tissue is feasible given a decisive joint effort between academia and collaborative healthcare groups, and with governmental support. An infrastructure for genomic analysis and prompt data output paves the way for novel systemic therapy for patients from all hospitals, irrespective of size and location.

Implementation of a digital preparation validation tool in dental skills laboratory training.

AIM: To describe the implementation of a digital tool for preparation validation and evaluate it as an aid in students' self-assessment. METHODS: Students at the final semester of skills laboratory training were asked to use a digital preparation validation tool (PVT) when performing two different tasks; preparation of crowns for teeth 11 and 21. The students were divided into two groups. Group A self-assessed and scanned all three attempts at 21 ("prep-and-scan"). Group B self-assessed all attempts chose the best one and scanned it ("best-of-three"). The situation was reversed for 11. The students assessed five parameters of the preparation and marked them as approved (A) or failed (F). These marks were compared with the information from the PVT. The students also completed a questionnaire. Each question was rated from 1 to 5. Teachers' opinions were collected at staff meetings throughout the project. RESULTS: Most students in the "prep-and-scan" groups showed an increase in agreement between their self-assessment and the information from the PVT, whereas students in the "best-of-three" groups showed lower levels of agreement. All students rated the PVT positively. Most strongly agreed that the tool was helpful in developing skills (mean 4.15), easy to use (mean 4.23) and that it added benefits in comparison to existing assessment tools (mean 4.05). They did not however, fully agree that the tool is time efficient (mean 2.55), and they did not consider it a substitute for verbal teacher feedback. Teachers' feedback suggested advantages of the tool in the form of ease of use, visual aid and increasing interest and motivation during skills laboratory training however, they did not notice a reduction in need of verbal feedback. CONCLUSIONS: Within the limitations of the study, our conclusion is that a digital PVT may be a valuable adjunct to other assessment tools in skills laboratory training.

Chronic pain in older adults: prevalence, incidence, and risk factors.

OBJECTIVES: Chronic pain is common in older adults, yet little is known of its development and the factors that predict its persistence and onset at old age. The aims of this longitudinal cohort study were to examine the prevalence and incidence of chronic pain and to explore possible risk factors for its persistence and onset in a representative sample of older Swedish adults. METHOD: Data were collected through questionnaires and followed up after 12 and 24 months. Chronic pain was defined as pain symptoms that lasted more than 3 months, regardless of the specific cause or site. Logistic regression analyses were used to identify odds ratios (ORs) with 95% confidence intervals (CIs) for potential predictors. RESULTS: Out of 2000 older adults approached (aged 65-103 years), 1141 were included in the study. Chronic pain was reported among 38.5% of the participants, and was more common among females and among adults over 85 years of age. The incidence was estimated to be 5.4% annually. Being female (OR 3.19, 95% CI 1.04-9.59), having a lower body mass index (BMI; OR 0.89, 95% CI 0.79-0.99), more than one pain location (OR 4.02, 95% CI 1.56-10.35), higher severity (OR 1.79, 95% CI 1.13-2.83), and longer duration (OR 1.08, 95% CI 1.01-1.15) were associated with the persistence of chronic pain, but this association did not remain significant for men when divided by gender. Younger age (OR 0.89, 95% CI 0.89-0.99) was associated with new onset of chronic pain. CONCLUSIONS: Even though pain was often highly prevalent and persistent, our results show that both recovery and onset of pain occurred. Pain characteristics, rather than age-related symptoms and psychosocial variables, predicted pain persistence among older women but not among older men. These findings highlight the importance of early pain management in the prevention of future pain.

Micromorphological differences of the implant-abutment junction and in vitro load testing for three different titanium abutments on Straumann tissue level implants.

BACKGROUND: The aim of this study was to investigate the micromorphological differences among three commercially available titanium abutments on Straumann implants. Furthermore, the possible impact of functional loading on the micromorphology and potential complications was investigated with the use of in vitro testing. MATERIAL AND METHODS: Three groups of Titanium abutments (A: Straumann Variobase n = 5, B: EBI best Duo n = 5, and C: Implant Direct n = 5) were torqued on Straumann RN implants, as according to each of the manufacturer's instructions. The implant-abutment units were scanned with Micro-CT. Three units of each group were directly sliced in the microtome and photographed under different magnifications (10×-500×) through a Scanning Electron Microscope. Six units (two from each group) were restored with cement-retained crowns, subjected to 2000,000 load cycles with loads between 30 and 300 N at 2 Hz, examined through Micro-CT and finally sliced and photographed as described above. The micromorphology of each unit was studied, and the total length of tight contact (<3 µm) was calculated between the implant, abutment and screw contact areas. RESULTS: Major morphological differences were identified between the three units, as well as differences in the extent of tight contact in all areas examined. Despite the morphological differences, the 2M cycles of loading via in vitro test did not result in any noticeable complications although some changes in the micromorphology were observed. CONCLUSION: The examined implant-abutment units presented with major morphological differences. Two million cycles of in vitro loading did not appear to affect the stability of the units despite the micromorphological changes. These results need to be interpreted however under the limitations of the small sample size and the specific set-up of the in vitro testing.

Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic.

BACKGROUND: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear. PATIENTS AND METHODS: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden. RESULTS: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years). CONCLUSIONS: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.

Strong and persistent effect on liver fat with a Paleolithic diet during a two-year intervention.

BACKGROUND/OBJECTIVES: Our objective was to investigate changes in liver fat and insulin sensitivity during a 2-year diet intervention. An ad libitum Paleolithic diet (PD) was compared with a conventional low-fat diet (LFD). SUBJECTS/METHODS: Seventy healthy, obese, postmenopausal women were randomized to either a PD or a conventional LFD. Diet intakes were ad libitum. Liver fat was measured with proton magnetic resonance spectroscopy. Insulin sensitivity was evaluated with oral glucose tolerance tests and calculated as homeostasis model assessment-insulin resistance (HOMA-IR)/liver insulin resistance (Liver IR) index for hepatic insulin sensitivity and oral glucose insulin sensitivity (OGIS)/Matsuda for peripheral insulin sensitivity. All measurements were performed at 0, 6 and 24 months. Forty-one women completed the examinations for liver fat and were included. RESULTS: Liver fat decreased after 6 months by 64% (95% confidence interval: 54-74%) in the PD group and by 43% (27-59%) in the LFD group (P<0.01 for difference between groups). After 24 months, liver fat decreased 50% (25-75%) in the PD group and 49% (27-71%) in the LFD group. Weight reduction between baseline and 6 months was correlated to liver fat improvement in the LFD group (rs=0.66, P<0.01) but not in the PD group (rs=0.07, P=0.75). Hepatic insulin sensitivity improved during the first 6 months in the PD group (P<0.001 for Liver IR index and HOMA-IR), but deteriorated between 6 and 24 months without association with liver fat changes. CONCLUSIONS: A PD with ad libitum intake had a significant and persistent effect on liver fat and differed significantly from a conventional LFD at 6 months. This difference may be due to food quality, for example, a higher content of mono- and polyunsaturated fatty acids in the PD. Changes in liver fat did not associate with alterations in insulin sensitivity.

A quantitative approach to analysing cortisol response in the horse.

The cortisol response to glucocorticoid intervention has, in spite of several studies in horses, not been fully characterized with regard to the determinants of onset, intensity and duration of response. Therefore, dexamethasone and cortisol response data were collected in a study applying a constant rate infusion regimen of dexamethasone (0.17, 1.7 and 17 µg/kg) to six Standardbreds. Plasma was analysed for dexamethasone and cortisol concentrations using UHPLC-MS/MS. Dexamethasone displayed linear kinetics within the concentration range studied. A turnover model of oscillatory behaviour accurately mimicked cortisol data. The mean baseline concentration range was 34-57 µg/L, the fractional turnover rate 0.47-1.5 1/h, the amplitude parameter 6.8-24 µg/L, the maximum inhibitory capacity 0.77-0.97, the drug potency 6-65 ng/L and the sigmoidicity factor 0.7-30. This analysis provided a better understanding of the time course of the cortisol response in horses. This includes baseline variability within and between horses and determinants of the equilibrium concentration-response relationship. The analysis also challenged a protocol for a dexamethasone suppression test design and indicated future improvement to increase the predictability of the test.

Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women.

BACKGROUND/OBJECTIVES: Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women. SUBJECTS/METHODS: Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11ß hydroxysteroid dehydrogenase type 1 (11ßHSD1) in subcutaneous adipose tissue were studied. RESULTS: Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11ßHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11ßHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months. CONCLUSIONS: Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.

Plasma concentration-dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone-21-isonicotinate.

Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03 mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 ± 2.9 days (LLOQ: 0.025 µg/L) and in urine for 9.8 ± 3.1 days (LLOQ: 0.15 µg/L). Maximum observed dexamethasone concentration in plasma was 0.61 ± 0.12 µg/L and in urine 4.2 ± 0.9 µg/L. Terminal plasma half-life was 38.7 ± 19 h. Hydrocortisone was significantly suppressed for 140 h. The plasma half-life of hydrocortisone was 2.7 ± 1.3 h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 ± 0.04 µg/L, 0.95 ± 0.04 and 6.2 ± 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.

The clinical success of tooth- and implant-supported zirconia-based fixed dental prostheses. A systematic review.

The aim was to make an inventory of the current literature on the clinical performance of tooth- or implant-supported zirconia-based FDPs and analyse and discuss any complications. Electronic databases, PubMed.gov, Cochrane Library and Science Direct, were searched for original studies reporting on the clinical performance of tooth- or implant-supported zirconia-based FDPs. The electronic search was complemented by manual searches of the bibliographies of all retrieved full-text articles and reviews, as well as a hand search of the following journals: International Journal of Prosthodontics, Journal of Oral Rehabilitation, International Journal of Oral & Maxillofacial Implants and Clinical Oral Implants Research. The search yielded 4253 titles. Sixty-eight potentially relevant full-text articles were retrieved. After applying pre-established criteria, 27 studies were included. Twenty-three studies reported on tooth-supported and 4 on implant-supported FDPs. Five of the studies were randomised, comparing Y-TZP-based restorations with metal-ceramic or other all-ceramic restorations. Most tooth-supported FDPs were FDPs of 3-5 units, whereas most implant-supported FDPs were full arch. The majority of the studies reported on 3- to 5-year follow-up. Life table analysis revealed cumulative 5-year survival rates of 93.5% for tooth-supported and 100% for implant-supported FDPs. For tooth-supported FDPs, the most common reasons for failure were veneering material fractures, framework fractures and caries. Cumulative 5-year complication rates were 27.6% and 30.5% for tooth- and implant-supported FDPs, respectively. The most common complications were veneering material fractures for tooth- as well as implant-supported FDPs. Loss of retention occurred more frequently in FDPs luted with zinc phosphate or glass-ionomer cement compared to those luted with resin cements. The results suggest that the 5-year survival rate is excellent for implant-supported zirconia-based FDPs, despite the incidence of complications, and acceptable for tooth-supported zirconia-based FDPs. These results are, however, based on a relatively small number of studies, especially for the implant-supported FDPs. The vast majority of the studies are not controlled clinical trials and have limited follow-up. Thus, interpretation of the results should be made with caution. Well-designed studies with large patient groups and long follow-up times are needed before general recommendations for the use of zirconia-based restorations can be provided.

microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is mainly initialised by receptor tyrosine kinase gene mutations. Although the tyrosine kinase inhibitor imatinib mesylate considerably improved the outcome of patients, imatinib resistance still remains a major therapeutic challenge in GIST therapy. Herein we evaluated the clinical impact of microRNAs in imatinib-treated GISTs. METHODS: The expression levels of microRNAs were quantified using microarray and RT-qPCR in GIST specimens from patients treated with neoadjuvant imatinib. The functional roles of miR-125a-5p and PTPN18 were evaluated in GIST cells. PTPN18 expression was quantified by western blotting in GIST samples. RESULTS: We showed that overexpression levels of miR-125a-5p and miR-107 were associated with imatinib resistance in GIST specimens. Functionally, miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous KIT mutation but not in GIST48 cells with double KIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, KIT mutational status and survival. CONCLUSIONS: Our findings highlight a novel functional role of miR-125a-5p on imatinib response through PTPN18 regulation in GIST.

Epidemiology and estimated costs of a large waterborne outbreak of norovirus infection in Sweden.

A large outbreak of norovirus (NoV) gastroenteritis caused by contaminated municipal drinking water occurred in Lilla Edet, Sweden, 2008. Epidemiological investigations performed using a questionnaire survey showed an association between consumption of municipal drinking water and illness (odds ratio 4·73, 95% confidence interval 3·53-6·32), and a strong correlation between the risk of being sick and the number of glasses of municipal water consumed. Diverse NoV strains were detected in stool samples from patients, NoV genotype I strains predominating. Although NoVs were not detected in water samples, coliphages were identified as a marker of viral contamination. About 2400 (18·5%) of the 13,000 inhabitants in Lilla Edet became ill. Costs associated with the outbreak were collected via a questionnaire survey given to organizations and municipalities involved in or affected by the outbreak. Total costs including sick leave, were estimated to be ∼8,700,000 Swedish kronor (∼€0·87 million).

High-frequency, high-intensity TENS compared to standard treatment with opioids for postoperative pain relief after laparoscopic cholecystectomy: A multicentre randomized controlled trial.

BACKGROUND: Adverse effects of opioids could prolong the duration of stay in the post-anaesthesia care unit (PACU). This study aimed to assess time in the PACU and the pain-relieving effect of high-frequency, high-intensity transcutaneous electrical nerve stimulation (HFHI TENS) versus standard treatment with intravenous (IV) opioids. METHODS: Patients undergoing laparoscopic cholecystectomy at two Swedish hospitals were invited to participate. Patients reporting postoperative pain intensity ≥3 according to the Numeric Rating Scale (NRS) in the PACU were randomized to receive standard treatment with IV opioids or HFHI TENS, administered with an intensity of 40-60 mA for 1 min, repeated once if insufficient pain relief. If NRS remained ≥3 after two TENS stimulation the patients received IV opioids. RESULTS: In total, 163 patients were randomized to receive HFHI TENS (n = 85) or IV opioids (n = 78). There was no difference between the HFHI TENS group versus the opioid group regarding time in the PACU (138 min [SD 69] vs. 142 min [SD 95], mean difference -4.42 [95% CI-30:22], p = 0.74), time to pain relief NRS < 3 (median 10 min) and pain intensity at PACU discharge (NRS 1.7 [SD 1.45] vs. 1.6 [SD 1.20], p = 0.58). In the HFHI TENS group, 39 patients (46%) needed additional treatment with IV opioids. Mean opioid consumption was significantly lower in the HFHI TENS group than in the opioid group (4.5 vs. 11.0 morphine equivalents; p < 0.001). CONCLUSIONS: HFHI TENS may be an opioid-sparing alternative for postoperative pain relief. SIGNIFICANCE STATEMENT: In this multicentre, RCT time in the PACU and the pain-relieving effect of HFHI TENS was compared to standard treatment with IV opioids. There were no differences between the groups regarding time in the PACU, time to pain relief and side effects but opioid consumption in the HFHI TENS group was significantly lower. Both groups reported high satisfaction with pain treatment and care. In summary, HFHI TENS should be considered a safe, fast-onsetting, opioid-sparing option for postoperative pain relief.

Comprehensive genomic analysis of adrenocortical carcinoma reveals genetic profiles associated with patient survival.

BACKGROUND: Adrenocortical carcinoma (ACC) is one of the most lethal endocrine malignancies and there is a lack of clinically useful markers for prognosis and patient stratification. Therefore our aim was to identify clinical and genetic markers that predict outcome in patients with ACC. METHODS: Clinical and genetic data from a total of 162 patients with ACC were analyzed by combining an independent cohort consisting of tumors from Yale School of Medicine, Karolinska Institutet, and Düsseldorf University (YKD) with two public databases [The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO)]. We used a novel bioinformatical pipeline combining differential expression and messenger RNA (mRNA)- and DNA-dependent survival. Data included reanalysis of previously conducted whole-exome sequencing (WES) for the YKD cohort, WES and RNA data for the TCGA cohort, and RNA data for the GEO cohort. RESULTS: We identified 3903 significant differentially expressed genes when comparing ACC and adrenocortical adenoma, and the mRNA expression levels of 461/3903 genes significantly impacted survival. Subsequent analysis revealed 45 of these genes to be mutated in patients with significantly worse survival. The relationship was significant even after adjusting for stage and age. Protein-protein interaction showed previously unexplored interactions among many of the 45 proteins, including the cancer-related proteins DNA polymerase delta 1 (POLD1), aurora kinase A (AURKA), and kinesin family member 23 (KIF23). Furthermore 14 of the proteins had significant interactions with TP53 which is the most frequently mutated gene in the germline of patients with ACC. CONCLUSIONS: Using a multiparameter approach, we identified 45 genes that significantly influenced survival. Notably, many of these genes have protein interactions not previously implicated in ACC. These findings may lay the foundation for improved prognostication and future targeted therapies.

A Palaeolithic-type diet causes strong tissue-specific effects on ectopic fat deposition in obese postmenopausal women.

OBJECTIVES: Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause. We hypothesized that a diet containing a relatively high content of protein and unsaturated fat [mainly monounsaturated fatty acids (MUFAs)] but limited carbohydrates and saturated fat would reduce lipid content in liver and muscle and increase insulin sensitivity in postmenopausal women. SUBJECTS: Ten healthy, nonsmoking postmenopausal women with a body mass index (BMI) >27 (28-35) kg m(-2) were included in the study. INTERVENTIONS: Participants were instructed to consume an ad libitum Palaeolithic-type diet intended to provide approximately 30 energy percentage (E%) protein, 40 E% fat (mainly MUFAs) and 30 E% carbohydrate. Intramyocellular lipid (IMCL) levels in calf muscles and liver triglyceride levels were quantified using proton magnetic resonance spectroscopy ((1) H-MRS) before and 5 weeks after dietary intervention. Insulin sensitivity was estimated by homoeostasis model assessment (HOMA) indices and the euglycaemic hyperinsulinaemic clamp technique. RESULTS: Mean energy intake decreased by 25% with a weight loss of 4.5 kg. BMI, waist and hip circumference, waist/hip ratio and abdominal sagittal diameter also decreased significantly, as did diastolic blood pressure (mean -7 mmHg), levels of fasting serum glucose, cholesterol, triglycerides, LDL/HDL cholesterol, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), urinary C-peptide and HOMA indices. Whole-body insulin sensitivity did not change. Liver triglyceride levels decreased by 49%, whereas IMCL levels in skeletal muscle were not significantly altered. CONCLUSIONS: A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women.

Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families.

The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.