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Abstract Background Engagement in Non-Suicidal Self-Injury (NSSI) is high among adolescents with borderline personality disorder (BPD), but the trajectory of NSSI in the transition period from adolescence to adulthood is unclear, and studies that look at predictors of persistence are highly needed. Methods This study followed 111 adolescents aged 14–17 with BPD over a five-year period to observe the prevalence and predictors of NSSI. Information on NSSI was based on both self-report and clinician-administered interviews. Results At the outset, 92.8% reported a history of NSSI, with an average of nearly five different types of NSSI. Despite this high initial prevalence, the rates of NSSI within the past two weeks decreased over time from 48% at baseline to 26% after one year, and further to 10% after two years. After five years, 37% reported engaging in NSSI within the past six months. Notably, all but one participant who reported NSSI after five years had engaged in NSSI already at baseline. The study identified that higher adolescent-rated but lower parent-rated BPD severity was associated with engagement in NSSI at baseline. Furthermore, ongoing NSSI after five years was predicted by lower parent-rated BPD severity and externalizing behaviors. Conclusions NSSI is frequent in the early course of BPD, and persists in more than one-third after five years. Our findings highlight that baseline engagement in NSSI is a risk factor for persistence of NSSI in the transition period into early adulthood. Furthermore, the findings underscore the significance of integrating both adolescent and parent perspectives on BPD pathology in the assessment and management of NSSI.

Background: Studies of the medium- to long-term clinical and functional course for treatment-seeking adolescents with borderline personality disorder (BPD) are lacking. This study aims to outline the psychopathological and functional status of participants, five years after being diagnosed with BPD during adolescence. Methods: Participants were originally enrolled in a randomized clinical trial that compared mentalization-based group treatment with treatment as usual for adolescents with BPD. Semi-structured interview assessments at five-year follow-up included the Schedules for Clinical Assessment in Neuropsychiatry and the Structured Clinical Interview for DSM-5 Personality Disorders. Attention deficit hyperactivity disorder (ADHD), alcohol, substance and tobacco use, posttraumatic stress disorder (PTSD), complex PTSD, and general functioning were assessed using self-report instruments. Results: 97 of the original sample of 111 participants (87%) participated. They were aged 19–23 years. The most prevalent disorders were ADHD (59%), any personality disorder (47%) of which half continued to meet criteria for BPD (24%), anxiety disorders (37%), depressive disorders (32%), PTSD or complex PTSD (20%), schizophrenia (16%), and eating disorders (13%). Only 16% did not meet criteria for any mental disorder. Approximately half of the sample were in psychological and/or psychopharmacological treatment at the time of follow-up. Their general functioning remained impaired, with 36% not engaged in education, employment or training (NEET), which is nearly four times the rate of NEET in the same age group in the general population. Conclusions: Although stability of the categorical BPD diagnosis is modest, adolescents meeting diagnostic criteria for BPD show a broad range of poor outcomes at five-year follow-up. BPD appears to be a marker of general maladjustment during adolescence and a harbinger of severe problems during the transition to young adulthood. Early intervention programs for adolescents diagnosed with BPD should focus upon a broad range of functional and psychopathological outcomes, especially social and vocational support, rather than the narrow BPD diagnosis.

Tissue inhibitor of metalloproteinases‐1 (TIMP‐1) regulates the proteolytic activity of matrix metalloproteinases (MMPs), playing an important role in the homeostasis of the extracellular matrix. Beyond its well‐known role in tissue maintenance, TIMP‐1 has been associated with multiple MMP‐independent cytokine‐like functions. The protein structure of TIMP‐1, with two distinct domains, one interacting with MMPs and another able to bind multiple partners, provides a rationale for this multifunctionality. The identification of CD63 as a cell surface receptor for TIMP‐1, able to mediate intracellular signaling through the Erk/MAPK axis, provided a molecular basis for the role of TIMP‐1 in cellular signaling. However, several lines of evidence suggest that TIMP‐1 may be able to associate with many interaction partners, thus attaining multiple functions. To enable the identification of previously unknown interaction partners that may underpin the core cellular functions of TIMP‐1, known as well as unknown, we performed a yeast two‐hybrid screening using a mammary gland complementary DNA (cDNA) library. We report here the identification of multiple interactors, including MHC class II‐associated invariant chain γ (CD74). We verified that CD74 interacts with TIMP‐1 in breast cancer cells and that this interaction contributes to cellular internalization of TIMP‐1 and mediates intracellular signaling through the Akt signaling axis in breast cancer cells. These data provide new insights into the complex nature of the functions of TIMP‐1 and their potential mechanistic basis.

Objective: Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. Methods: Our focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N = 99) received NN1177 (on an escalating dose regimen of 200, 600, 1300, 1900, 2800, 4200 and 6000 μg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N = 49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1100 μg) or placebo, and a drug–drug interaction, open-label, single-sequence trial in which adults (N = 45) received a 4200-μg dose of NN1177, following administration of a Cooperstown 5 + 1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed. Results: For the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 h, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4200 μg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids. Conclusion: Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.

Abstract Background There is a dearth of studies evaluating treatment efficacy for adolescents diagnosed with borderline personality disorder. The few available randomized controlled trials that have been conducted show modest results and treatments appear to have equivalent effects. The current paper draws on (a) the lessons learnt from the last 50 years of psychotherapy research in general and (b) recent advances in mentalization-based understanding of why treatment works, which together point to the importance of following a socioecological approach in the treatment of personality problems in adolescence – a developmental period that insists on a treatment approach that goes beyond the therapist-client dyad. Case presentation Here, we describe such an approach, and offer a clinical case example with a young 16-year old girl diagnosed with borderline personality disorder, to illustrate what a shift toward a more socioecological approach would entail. Conclusions The clinical impact of the socioecological approach and the potential benefits as illustrated in the current case illustration, offers a framework that justifies and allows for the expansion of service delivery for youth with borderline personality disorder beyond dyadic therapist-client work.

Abstract High frequency industrial induction heating processes typically employ resonant inverters to reach high efficiency at high power levels. Advancements in wide band gap (WBG) device technology has made it feasible to push the possible frequency of these processes into the MHz regime using solid state technology. Several topologies can be applied, each with advantages and drawbacks. This paper presents a current source resonant inverter (CSRI) employing a custom designed power module utilizing 1700V SiC MOSFETs for MHz operation of a high‐Q resonant tank for induction heating, which presents new challenges in the inverter module design. An integrated gate driver structure is demonstrated driving four MOSFETs in parallel in MHz operation. Theoretical analysis predicts substantial parasitic influence on inverter operation, and thus an inverter is constructed to provide experimental verification of MHz operation, while the challenges associated with high frequency CSRI operation are discussed. In the experimental inverter setup, the fabricated power module achieves >90% efficiency for a calculated reactive power of 170 kVA and 2.3 kW output power during unloaded operation, validating the inverter design for extension to higher power loaded operation.

Personality disorder (PD) has been and continues to be a controversial mental disorder to discuss with young people under the age of 18 [...]

Borderline personality disorder (BPD) is characterized by severe disturbances related to understanding oneself and other people and can be reliably detected and treated in adolescence. In this feasibility study, we aimed to focus on the features of, and changes in, narrative identity throughout the course of Mentalization-Based Treatment in Groups (MBT-G) for adolescents with BPD. Six female patients (M = 15.2, SD = 0.75) joined between 16 and 31 (M = 23.83) MBT g sessions. The narrated events within each session across sessions were coded for themes of agency and communion and the narrated reactions were coded for personality functioning. The patients and their parents also completed several self-report measures before and after therapy. Themes of diminished agency and communion were identified, with communion as the dominating theme. When comparing the patients’ first five sessions with their last five sessions, there was an increase in themes related to agency and decreased in communion. The narrated reactions were dominated by themes related to thwarted self-functioning and primarily identity, although intimacy was also present. Patients improved in terms of self-reported functioning and internalizing and externalizing behavior before and after end of treatment. The importance of narration in BPD (group) therapy is discussed alongside clinical implications.

The 11th revision of the International Classification of Diseases for Mortality and Morbidity Statistics (ICD-11) defines personality disorder according to personality functioning, which relates to self- and interpersonal functioning. The aim of the present study was to assess the relationship between mentalizing and personality functioning in patients with subthreshold or diagnosed borderline personality disorder. A total of 116 eligible participants were included. Mentalizing was assessed using the Mentalization Questionnaire (MZQ), personality functioning (self- and interpersonal functioning) was assessed using the Level of Personality Functioning Scale-Brief Form 2.0 (LPFS-BF), and borderline severity was assessed using the Zanarini Rating Scale (ZAN-BPD). Mediation analysis was employed to test if mentalizing accounted for the relationship between borderline severity and self- and interpersonal functioning. We found a significant relationship between borderline severity and both subscales of the LPFS-BF. Mentalizing fully and significantly mediated the relationship between borderline severity and interpersonal functioning. However, mentalizing only partly mediated the relationship between borderline severity and self-functioning. Controlling for the covariates gender and age did not impact the results. Mentalizing is likely to be involved in the ICD-11 model of personality functioning, especially interpersonal functioning. This could emphasize the relevance of therapy aimed at strengthening mentalizing abilities when treating personality pathology in general and people with borderline personality disorder in particular. However, self-functioning may be more nuanced, as aspects other than mentalizing also influence self-functioning. The study is explorative in nature and has methodological limitations that require caution in the interpretation and generalizability.

Background: Congenital hyperinsulinism (CHI), a rare disease of excessive and dysregulated insulin secretion, can lead to prolonged and severe hypoglycemia. Dextrose infusions are a mainstay of therapy to restore normal glycemia, but can be associated with volume overload, especially in infants. By releasing intrahepatic glucose stores, glucagon infusions can reduce dependency on dextrose infusions. Recent studies have reported positive outcomes with glucagon infusions in patients with CHI; however, to date, there are no reports describing the clinical utility of titrated doses of infused glucagon to achieve glycemic stability.Objective: To assess the potential clinical utility of dose-titrated glucagon infusions in stabilizing glycemic status in pediatric patients with CHI, who were managed by medical and/or surgical approaches.Methods: Patients with CHI (N = 33), with or without mutations in the ATP-sensitive K+ channel genes, ABCC8, and KCNJ11 requiring glucagon by dose titration in addition to intravenous dextrose and medical therapy with diazoxide/octreotide to achieve glycemic stability were recruited. Following glucagon titration and a 24-h glucose stable period, glucose infusion rate (GIR) was reduced over a 24-h period. Achievement of glycemic stability and decrease in GIR were considered end points of the study.Results: All patients achieved glycemic stability with glucagon infusion, demonstrating clinical benefit. GIR reduced from 15.6 (4.5) to 13.4 (4.6) mg/kg/min mean (SD) (p = 0.00019 for difference; n = 32; paired t-test) over 24 h. By univariate analysis, no individual baseline characteristic was associated with changes in the GIR. However, by baseline-adjusted modeling, mutational status of the patient (p = 0.011) was inversely associated with a reduction in GIR. Adverse events were infrequent with diarrhea possibly attributed to glucagon treatment in 1 patient. With long-term treatment following GIR reduction, necrolytic migratory erythema was observed in another patient.Conclusion: These data suggest that dose-titrated glucagon infusion therapy aids hypoglycemia prevention and reduction in GIR in the clinical management of patients with CHI.

Abstract Background Insecure attachment is a precursor and correlate of borderline personality disorder. According to the mentalization-based theory of borderline personality disorder, the presence of insecure attachment derails the development of the capacity to mentalize, potentially resulting in borderline pathology. While one prior study found support for this notion in adolescents, it neglected a focus on peer attachment. Separation from primary caregivers and formation of stronger bonds to peers are key developmental achievements during adolescence and peer attachment warrants attention as a separate concept. Findings In a cross-sectional study, female outpatients (Mage 15.78=, SD = 1.04) who fulfilled DSM-5 criteria for BPD (N = 106) or met at least 4 BPD criteria (N = 4) completed self-reports on attachment to parents and peers, mentalizing capacity (reflective function) and borderline personality features. Our findings suggest that in a simple mediational model, mentalizing capacity mediated the relation between attachment to peers and borderline features. In the case of attachment to parents, the mediational model was not significant. Conclusions The current study is the first to evaluate this mediational model with parent and peer attachment as separate concepts and the first to do so in a sample of adolescents who meet full or sub-threshold criteria for borderline personality disorder. Findings incrementally support that mentalizing capacity and attachment insecurity, also in relation to peers, are important concepts in theoretical approaches to the development of borderline personality disorder in adolescence. Clinical implications are discussed.

This study aims to simulate the use of renewable energy in the form of different energy sources, such as solar cells, district heating, and in the presence of battery storage and for high penetration of electric vehicles in a typical Swedish power grid. The EnergyPLAN software is used. The purpose is to examine the demands in order to cope with the needs that may arise and to create a better understanding of how renewable energy affects the power balance and future investments in the case of a typical Swedish distribution system. The importance of this research is mainly based on the fact that it represents a real network, as it operates today, which is analyzed using the expected electric vehicle penetration. The aim is to investigate the expansion needs for maintaining the current quality for service despite the addition of new loads. In addition, the regional and national special regulatory and operational requirements are taken into account and described in this work.

The act of naming is among the most basic actions of language. Indeed, it is naming something that enables us to communicate about it in specific terms, whether the object named is human or non-human, animate or inanimate. However, naming is not as uncomplicated as we may usually think and names have consequences for the way we think about animals (human and non-human), peoples, species, places, things etc. Through a blend of history, philosophy and representational theory—and using examples from, among other things, the Bible, Martin Luther, colonialism/imperialism and contemporary ways of keeping and regarding non-human animals—this paper attempts to trace the importance of (both specific and generic) naming to our relationships with the non-human. It explores this topic from the naming of the animals in Genesis to the names given and used by scientists, keepers of companion animals, media etc. in our societies today, and asks the question of what the consequences of naming non-human animals are for us, for the beings named and for the power relations between our species and the non-human species and individuals we name.

Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and, unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I inhibitors and topoisomerase I as a potential predictive biomarker as case in point.

BackgroundTopoisomerase I (Top1) is the target of Top1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH).MethodsNine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined.ResultsTOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20ConclusionsTOP1 gene copy number increase occurs frequently in stage III CRC in a mechanism that often includes CEN-20. Using CEN-2 as a measurement for tumor ploidy levels, we were able to discriminate between different mechanisms of gene gain, which appeared to differ in prognostic impact. TOP1 FISH guidelines have been updated.

Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response.The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively.58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29).Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women.ClinicalTrials.gov NCT01012557.

BackgroundMicroRNA (miRNA) expression is broadly altered in cancer, but few studies have investigated miRNA deregulation in oral squamous cell carcinoma (OSCC). Epigenetic mechanisms are involved in the regulation of >30 miRNA genes in a range of tissues, and we aimed to investigate this further in OSCC.MethodsTaqMan® qRT-PCR arrays and individual assays were used to profile miRNA expression in a panel of 25 tumors with matched adjacent tissues from patients with OSCC, and 8 control paired oral stroma and epithelium from healthy volunteers. Associated DNA methylation changes of candidate epigenetically deregulated miRNA genes were measured in the same samples using the MassArray® mass spectrometry platform. MiRNA expression and DNA methylation changes were also investigated in FACS sorted CD44(high) oral cancer stem cells from primary tumor samples (CSCs), and in oral rinse and saliva from 15 OSCC patients and 7 healthy volunteers.ResultsMiRNA expression patterns were consistent in healthy oral epithelium and stroma, but broadly altered in both tumor and adjacent tissue from OSCC patients. MiR-375 is repressed and miR-127 activated in OSCC, and we confirm previous reports of miR-137 hypermethylation in oral cancer. The miR-200 s/miR-205 were epigenetically activated in tumors vs normal tissues, but repressed in the absence of DNA hypermethylation specifically in CD44(high) oral CSCs. Aberrant miR-375 and miR-200a expression and miR-200c-141 methylation could be detected in and distinguish OSCC patient oral rinse and saliva from healthy volunteers, suggesting a potential clinical application for OSCC specific miRNA signatures in oral fluids.ConclusionsMiRNA expression and DNA methylation changes are a common event in OSCC, and we suggest miR-375, miR-127, miR-137, the miR-200 family and miR-205 as promising candidates for future investigations. Although overall activated in OSCC, miR-200/miR-205 suppression in oral CSCs indicate that cell specific silencing of these miRNAs may drive tumor expansion and progression.