Penile Cancers Attributed to Human Papillomavirus Are Associated with Improved Survival for Node-positive Patients. Findings from a Norwegian Cohort Study Spanning 50 Years.

BACKGROUND: Human papillomavirus (HPV) infection is a risk factor for the development of penile squamous cell carcinoma (PSCC). It remains inconclusive whether HPV-related PSCC has a different prognosis from non-HPV-related PSCC. OBJECTIVE: To investigate the relationship between HPV status and survival as well as temporal changes in the proportion of HPV-related PSCC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort of 277 patients treated in Norway between 1973 and 2022 was investigated for HPV DNA in tumor tissue. Clinicopathological variables and disease course were registered. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier curves and Cox regression were used to investigate the determinants of cancer-specific survival (CSS). The chi-square test for trend in proportions enabled investigation of temporal changes in the HPV-related proportion of PSCC patients treated in Western Norway (n = 211). RESULTS AND LIMITATIONS: HPV DNA was detected in tumor tissue from 131 (47%) patients. Stratified by HPV status, 5-yr CSS did not differ between groups (p = 0.37). When investigating only node-positive patients, however, presence of HPV DNA was an independent predictor of better survival in multivariable Cox regression after adjustment for age, nodal stage, and adjuvant therapy (hazard ratio 0.54, 95% confidence interval: [0.30-0.99], p = 0.04). In cases from Western Norway, an increasing proportion of HPV-related cases over time was found (p = 0.01). The main limitation is the retrospective study design. CONCLUSIONS: HPV DNA in tumor tissue was associated with significantly better CSS for node-positive patients. The proportion of HPV DNA-positive PSCC has increased significantly in Western Norway over the past 50 yr. PATIENT SUMMARY: We investigated the impact of human papillomavirus (HPV) on the survival of penile cancer patients treated over a 50-yr period in Norway. We found that for patients with lymph node metastasis, survival was better for HPV-related cases. We also found that the proportion of cases due to HPV has increased in Western Norway.

Childhood trauma, antipsychotic medication, and symptom remission in first-episode psychosis.

BACKGROUND: To what extent psychotic symptoms in first-episode psychosis (FEP) with a history of childhood interpersonal trauma (CIT) are less responsive to antipsychotic medication is not known. In this longitudinal study, we compare symptom trajectories and remission over the first 2 years of treatment in FEP with and without CIT and examine if differences are linked to the use of antipsychotics. METHODS: FEP (N = 191) were recruited from in- and outpatient services 1997-2000, and assessed at baseline, 3 months, 1 and 2 years. Inclusion criteria were 15-65 years, actively psychotic with a DSM-IV diagnosis of psychotic disorder and no previous adequate treatment for psychosis. Antipsychotic medication is reported as defined daily dosage (DDD). CIT (<18) was assessed with the Brief Betrayal Trauma Survey, and symptomatic remission based on scores from the Positive and Negative Syndrome Scale. RESULTS: CIT (n = 63, 33%) was not associated with symptomatic remission at 2 years follow-up (71% in remission, 14% in relapse), or time to first remission (CIT 12/ no-CIT 9 weeks, p = 0.51). Those with CIT had significantly more severe positive, depressive, and excited symptoms. FEP with physical (N = 39, 20%) or emotional abuse (N = 22, 14, 7%) had higher DDD at 1 year (p < 0.05). Mean DDD did not excerpt a significant between-group effect on symptom trajectories of positive symptoms. CONCLUSION: Results indicate that antipsychotic medication is equally beneficial in the achievement of symptomatic remission in FEP after 2 years independent of CIT. Still, FEP patients with CIT had more severe positive, depressive, and excited symptoms throughout.

Depression trajectories and cytokines in schizophrenia spectrum disorders - A longitudinal observational study.

Depression occurs frequently in all phases of schizophrenia spectrum disorders. Altered activity in the immune system is seen in both depression and schizophrenia. We aimed to uncover depressive trajectories in a sample of 144 adult individuals with schizophrenia spectrum disorders followed for one year, in order to identify possible cytokine profile differences. Patients were assessed longitudinally with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), where a score above 6 predicts depression. The serum cytokine concentrations for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70 and IL-17A were measured using immunoassays. Latent growth curve models, multilevel models and latent class growth analysis (LCGA) were applied. The LCGA model supported three latent classes (trajectories) with differing CDSS profiles during the one-year follow-up: a high CDSS group (40.8 % of participants), a moderate CDSS group (43.9 %) and a low CDSS group (15.3 %). Five single PANSS items predicted affiliation to depressive trajectory: hallucinations, difficulty in abstract thinking, anxiety, guilt feelings and tension. In the high CDSS group, despite diminishing psychotic symptoms, depressive symptoms persisted throughout one year. The pro-inflammatory cytokines IFN-γ, IL-1ß and TNF-α were differentially distributed between the depressive trajectories, although levels remained remarkably stable throughout 12 months. Significant changes were found for the anti-inflammatory cytokine IL-10 at baseline with an accompanying difference in change over time. More research is required to optimize future treatment stratification and investigate the contribution of inflammation in depressed patients with schizophrenia spectrum disorders.

Nonoperative or Surgical Treatment of Acute Achilles' Tendon Rupture.

BACKGROUND: Whether surgical repair of an acute Achilles' tendon rupture by an open-repair or minimally invasive approach is associated with better outcomes than nonsurgical treatment is not clear. METHODS: We performed a multicenter, randomized, controlled trial that compared nonoperative treatment, open repair, and minimally invasive surgery in adults with acute Achilles' tendon rupture who presented to four trial centers. The primary outcome was the change from baseline in the Achilles' tendon Total Rupture Score (scores range from 0 to 100, with higher scores indicating better health status) at 12 months. Secondary outcomes included the incidence of tendon rerupture. RESULTS: A total of 554 patients underwent randomization, and 526 patients were included in the final analysis. The mean changes in the Achilles' tendon Total Rupture Score were -17.0 points in the nonoperative group, -16.0 points in the open-repair group, and -14.7 points in the minimally invasive surgery group (P = 0.57). Pairwise comparisons provided no evidence of differences between the groups. The changes from baseline in physical performance and patient-reported physical function were similar in the three groups. The number of tendon reruptures was higher in the nonoperative group (6.2%) than in the open-repair or minimally invasive surgery group (0.6% in each). There were 9 nerve injuries in the minimally invasive surgery group (in 5.2% of the patients) as compared with 5 in the open-repair group (in 2.8%) and 1 in the nonoperative group (in 0.6%). CONCLUSIONS: In patients with Achilles' tendon rupture, surgery (open repair or minimally invasive surgery) was not associated with better outcomes than nonoperative treatment at 12 months. (Funded by the South-Eastern Norway Regional Health Authority and Akershus University Hospital; ClinicalTrials.gov number, NCT01785264.).

Association between C-reactive protein levels and antipsychotic treatment during 12 months follow-up period after acute psychosis.

BACKGROUND: A potential role of inflammatory pathways in the pathology of schizophrenia has been suggested for at least a subgroup of patients. Elevated levels of the inflammatory marker C-reactive protein (CRP) have been observed, with associations to pathogenesis and symptoms. The current evidence regarding effects of antipsychotics on CRP levels is ambiguous. OBJECTIVES: To examine and compare the influence on CRP levels of three pharmacologically diverse new generation antipsychotics during a one-year follow-up in schizophrenia spectrum disorder. METHODS: In a multicenter, pragmatic and rater-blinded randomized trial, the effects of amisulpride, aripiprazole and olanzapine were compared in 128 patients with schizophrenia spectrum disorder. All had positive symptoms of psychosis at study entry. Clinical and laboratory assessments including the measurement of CRP levels were conducted at baseline, and 1, 3, 6, 12, 26, 39, and 52 weeks thereafter. RESULTS: For all antipsychotic drugs analysed together, there was an increase in CRP levels during the one-year follow-up. Aripiprazole, as opposed to amisulpride and olanzapine, was associated with a reduced CRP level after one week, after which the CRP level caught up with the other drugs. Compared to those previously exposed to antipsychotic drugs, antipsychotic-naïve patients had lower CRP levels at all follow-up time points, but with the same temporal patterns of change. CONCLUSION: Treatment with amisulpride, aripiprazole and olanzapine showed different effects on CRP levels in patients with schizophrenia spectrum disorders, modified by previous antipsychotics exposure status. This finding suggests that antipsychotic drugs may vary with respect to their influence on pro-inflammatory pathways. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01446328; URL: http://www. CLINICALTRIALS: gov/.

Sex differences in antipsychotic efficacy and side effects in schizophrenia spectrum disorder: results from the BeSt InTro study.

Current guidelines for patients with schizophrenia spectrum disease do not take sex differences into account, which may result in inappropriate sex-specific treatment. In the BeSt InTro study, a total of 144 patients (93 men and 51 women) with a schizophrenia spectrum diagnosis and ongoing psychosis were included and randomized to amisulpride, aripiprazole, or olanzapine in flexible dose. This trial is registered with ClinicalTrials.gov (NCT01446328). Primary outcomes were sex differences in dose, dose-corrected serum levels, efficacy, and tolerability. Dosing was higher for men than for women in the aripiprazole group (p = 0.025) and, at trend level, in the olanzapine group (p = 0.056). Dose-corrected serum levels were 71.9% higher in women than in men for amisulpride (p = 0.019) and 55.8% higher in women than in men for aripiprazole (p = 0.049). In the amisulpride group, men had a faster decrease in psychotic symptoms than women (p = 0.003). Moreover, amisulpride was more effective than the other medications in men but not in women. Prolactin levels were higher in women than in men, especially for amisulpride (p < 0.001). Also, women had higher BMI increase on amisulpride compared to the two other antipsychotics (p < 0.001). We conclude that clinicians should be aware of the risks of overdosing in women, especially for amisulpride and aripiprazole. Amisulpride is highly effective in men, but in women, amisulpride showed more severe side effects and may thus not be the drug of first choice. Our study shows that sex differences should be taken into account in future studies on antipsychotics. Future research is warranted to evaluate these preliminary results.

Do cells sense time by number of divisions?

Can the cell's perception of time be expressed through the length of the shortest telomere? To address this question, we analyze an asymmetric random walk that models telomere length for each division that can decrease by a fixed length a or, if recognized by a polymerase, it increases by a fixed length b ≫ a. Our analysis of the model reveals two phases, first, a determinist drift of the length toward a quasi-equilibrium state, and second, persistence of the length near an attracting state for the majority of divisions. The measure of stability of the latter phase is the expected number of divisions at the attractor ("lifetime") prior to crossing a threshold T that model senescence. Using numerical simulations, we further study the distribution of times for the shortest telomere to reach the threshold T. We conclude that the telomerase regulates telomere stability by creating an effective potential barrier that separates statistically the arrival time of the shortest from the next shortest to T. The present model explains how random telomere dynamics underlies the extension of cell survival time.

"Everyone Needs a Friend Sometimes" - Social Predictors of Long-Term Remission In First Episode Psychosis.

Background: Predictors of long-term symptomatic remission are crucial to the successful tailoring of treatment in first episode psychosis. There is lack of studies distinguishing the predictive effects of different social factors. This prevents a valid evaluating of their independent effects. Objectives: To test specific social baseline predictors of long-term remission. We hypothesized that first, satisfaction with social relations predicts remission; second, that frequency of social interaction predicts remission; and third, that the effect of friend relationship satisfaction and frequency will be greater than that of family relations satisfaction and frequency. Material and Methods: A sample of first episode psychosis (n = 186) completed baseline measures of social functioning, as well as clinical assessments. We compared groups of remitted and non-remitted individuals using generalized estimating equations analyses. Results: Frequency of social interaction with friends was a significant positive predictor of remission over a two-year period. Neither global perceived social satisfaction nor frequency of family interaction showed significant effects. Conclusions: The study findings are of particular clinical importance since frequency of friendship interaction is a possibly malleable factor. Frequency of interaction could be affected through behavioral modification and therapy already from an early stage in the course, and thus increase remission rates.

Obstacles to care in first-episode psychosis patients with a long duration of untreated psychosis.

AIM: This qualitative study is a sub-study of the early 'Treatment and Intervention in Psychosis Study' (TIPS-2), a program for early intervention strategies for people experiencing a first episode of psychosis. We aimed to improve knowledge about factors that prevent or delay patients with a long duration of psychosis from accessing psychiatric health-care services at an earlier illness stage and their personal views on the impact of ongoing informational campaigns (ICs) on help-seeking behaviour. METHOD: Following an interpretative-phenomenological approach, eight consecutive TIPS-2 patients with duration of untreated psychosis lasting for more than 6 months were interviewed. The interviews were analysed using a meaning condensation procedure. RESULTS: Five main themes were identified: (i) participants' failure to recognize symptoms of psychosis; (ii) difficulties expressing their experiences; (iii) concerns about stigma; (iv) poor psychosis detection skills among health-care professionals; and (v) participants' lack of awareness or understanding of ICs. CONCLUSIONS: The five themes identified may suggest that despite exposure to the targeted ICs, participants were unable to recognize or understand the severity of their symptoms. Further, although family members or others sometimes recognized the initial symptoms of psychosis development, these symptoms were attributed to reasons other than psychosis. Participants reported that health-care personnel also had trouble identifying emerging signs of psychosis. The ICs need to be carefully crafted to relay information to people who do not consider themselves as currently experiencing signs of psychosis.

Variation in duration of untreated psychosis in an 18-year perspective.

AIM: The Scandinavian TIPS project engineered an early detection of psychosis programme that sought to reduce the duration of untreated psychosis (DUP) through early detection teams and extensive information campaigns since 1997. In 1997-2000, DUP was reduced from 26 to 4.5 weeks median. The programme was continued beyond the initial project in modified forms for over 13 years. The aim of this study was to track the vicissitudes of DUP over an 18-year period (1993-2010) with differing early detection efforts in a defined catchment area. METHOD: The DUP of all patients meeting criteria for first episode psychosis was measured 1993-1994 and from 1997 to 2010 in a naturalistic long-term study. DUP values of all patients were included, irrespective of patients' participation in a clinical follow-up study, yielding a highly representative sample. RESULTS: DUP varied across studies with differing information campaign intensity and content. These variations will be described and explored. CONCLUSIONS: Early detection campaigns should have a stable focus and high intensity level. Future research should further elucidate pathways to care in order to establish principal targets for information campaigns.

Impact of interpersonal trauma on the social functioning of adults with first-episode psychosis.

BACKGROUND: Social functioning is an important treatment outcome for psychosis, and yet, we know little about its relationship to trauma despite high rates of trauma in people with psychosis. Childhood trauma is likely to disrupt the acquisition of interpersonal relatedness skills including the desire for affiliation and thus lead to impaired social functioning in adulthood. AIMS: We hypothesized that childhood trauma would be a predictor of poor social functioning for adults with psychosis and that further trauma in adulthood would moderate this relationship. METHOD: A first-episode psychosis sample aged 15-65 years (N = 233) completed measures of social functioning (Lehman's Quality of Life Interview and Strauss Carpenter Functioning Scale) and trauma (Brief Betrayal Trauma Survey), as well as clinical assessments. RESULTS: Childhood trauma (any type) was associated with poorer premorbid functioning and was experienced by 61% of our sample. There were no associations with clinical symptoms. Interpersonal trauma in childhood was a significant predictor of social functioning satisfaction in adulthood, but this was not the case for interpersonal trauma in adulthood. However, 45% of adults who reported childhood interpersonal trauma also experienced adulthood interpersonal trauma. CONCLUSION: Our results emphasize the importance of early relationship experience such as interpersonal trauma, on the social functioning of adults with psychosis. We recommend extending our research by examining the impact of interpersonal childhood trauma on occupational functioning in psychosis.

Ten year neurocognitive trajectories in first-episode psychosis.

OBJECTIVE: Neurocognitive impairment is commonly reported at onset of psychotic disorders. However, the long-term neurocognitive course remains largely uninvestigated in first episode psychosis (FEP) and the relationship to clinically significant subgroups even more so. We report 10 year longitudinal neurocognitive development in a sample of FEP patients, and explore whether the trajectories of cognitive course are related to presence of relapse to psychosis, especially within the first year, with a focus on the course of verbal memory. METHOD: Forty-three FEP subjects (51% male, 28 ± 9 years) were followed-up neurocognitively over five assessments spanning 10 years. The test battery was divided into four neurocognitive indices; Executive Function, Verbal Learning, Motor Speed, and Verbal Fluency. The sample was grouped into those relapsing or not within the first, second and fifth year. RESULTS: The four neurocognitive indices showed overall stability over the 10 year period. Significant relapse by index interactions were found for all indices except Executive Function. Follow-up analyses identified a larger significant decrease over time for the encoding measure within Verbal Memory for patients with psychotic relapse in the first year [F (4, 38) = 5.8, p = 0.001, η(2) = 0.40]. CONCLUSIONS: Main findings are long-term stability in neurocognitive functioning in FEP patients, with the exception of verbal memory in patients with psychotic relapse or non-remission early in the course of illness. We conclude that worsening of specific parts of cognitive function may be expected for patients with on-going psychosis, but that the majority of patients do not show significant change in cognitive performance during the first 10 years after being diagnosed.

Low-fouling, biospecific films prepared by the continuous assembly of polymers.

We report that the continuous assembly of polymers (CAP) approach, mediated by ring-opening metathesis polymerization (ROMP), is a facile and versatile technology to prepare engineered nanocoatings for various biomedical applications. Low-fouling coatings on particles were obtained by the formation of multicompositional, layered films via simple and efficient tandem CAP(ROMP) processes that are analogous to chain extension reactions. In addition, the CAP(ROMP) approach allows for the efficient postfunctionalization of the CAP films with bioactive moieties via cross-metathesis reactions between the surface-immobilized catalysts and symmetrical alkene derivatives. The combined features of the CAP(ROMP) approach (i.e., versatile polymer selection and facile functionalization) allow for the fabrication and surface modification of various types of polymer films, including those with intrinsic protein-repellent properties and selective protein recognition capabilities. This study highlights the various types of advanced coatings and materials that the CAP approach can be used to generate, which may be useful for biomedical applications.

Factors associated with involuntary admissions among patients with substance use disorders and comorbidity: a cross-sectional study.

BACKGROUND: To investigate factors associated with involuntary admissions to hospital pursuant to a social services act of patients with substance use disorder by comparing the socio-demographic characteristics, substance use, and psychiatric comorbidities with voluntarily admitted patients. METHODS: This cross-sectional study compared two groups admitted to combined substance use disorder and psychiatry wards. Sixty-five patients were involuntarily admitted pursuant to the Social Services Act and 137 were voluntarily admitted. The International Classification of Diseases and Related Health Problems was used for diagnostic purposes regarding substance use disorders, type and severity of psychiatric problems, and level of functioning. Socio-demographic variables were measured using the European Addiction Severity Index, and the Symptom Checklist-90-R instruments were used to evaluate the range of psychological problems and psychopathological symptoms. Logistic regression was performed to investigate the relationship between involuntary admissions and patients characteristics. RESULTS: Patients who had been involuntarily admitted were more likely to be females, had utilized public welfare services more often, presented more severe substance use patterns, and had a history of more frequent visits to physicians for somatic complaints in the last 6 months, they also had fewer comorbid mental disorders. Still, considerable burdens of comorbid substance use disorders and mental disorders were observed both among involuntary and voluntary admitted patients. CONCLUSIONS: More attention is required for involuntarily admitted patients in order to meet the needs associated with complex and mixed disorders. In addition, treatment centers should offer diagnostic options and therapy regarding substance use, psychiatric and somatic disorders.

Early detection, early symptom progression and symptomatic remission after ten years in a first episode of psychosis study.

BACKGROUND: Poor symptom outcome remains a challenge in psychosis: At least 50% of first-episode patients continue to have positive and/or negative symptoms after ten years. OBJECTIVE: To investigate rates, early predictors and early symptom progression of long-term non-remitted psychosis in an early detection study. METHODS: Symptomatic remission according to new international criteria was assessed in 174 patients at ten-year follow-up. Remitted and non-remitted patients were compared on early symptom progression, and logistic regression was applied to predict non-remission. RESULTS: At ten years, 50% of patients were in symptomatic remission. Non-remission was predicted by positive symptoms at inclusion and during the first year of treatment. Of individual symptoms only hallucinations were significantly predictive of ten-year non-remission. Early symptom differences were not reflected by differences in treatment. CONCLUSIONS: Long-term symptomatic non-remission is associated with early positive symptoms. More assertive intervention may be needed in patients who do not respond robustly in the first year of treatment, whether or not they have been detected "early".

The relationship of verbal learning and verbal fluency with written story production: implications for social functioning in first episode psychosis.

BACKGROUND: Impairments in speech, communication and Theory of Mind are common in schizophrenia, and compromise social functioning. Some of these impairments may already be present pre-morbidly. This study aimed to investigate verbal functions in relation to written story production and social functioning in people experiencing a first episode of psychosis (FEP). METHOD: Two groups of participants: FEP (N=31) and healthy controls (HC, N=31), completed measures of clinical status, social functioning, a series of neuropsychological tests targeting verbal functioning, and the "Frog Where Are You?" story production task. RESULTS: Story results showed reduced efficiency (words per minute) and self-monitoring (corrections per minute) for FEP compared with HC groups (p<0.01). The FEP group performed significantly poorer than the HC group on most indices of verbal learning and verbal fluency. Story production was positively associated with verbal learning and verbal fluency for the FEP group only (p<0.05). Premorbid function decline was associated with impaired verbal learning and memory for the FEP group. CONCLUSION: Individuals with FEP show a childhood history of reduced social and academic performance that is associated with skills essential for daily social interactions, as evidenced by the findings for story production, verbal learning and verbal fluency.

A comparison of adolescent- and adult-onset first-episode, non-affective psychosis: 2-year follow-up.

This study aimed to compare 2-year outcome among individuals with early-onset (EO; <18 years) versus adult-onset (AO) first-episode, non-affective psychosis. We compared clinical and treatment characteristics of 43 EO and 189 AO patients 2 years after their inclusion in a clinical epidemiologic population-based cohort study of first-episode psychosis. Outcome variables included symptom severity, remission status, drug abuse, treatment utilization, cognition and social functioning. At baseline, EO patients were more symptomatically compromised. However, these initial baseline differences were no longer significant at the 2-year follow-up. This study challenges the findings of a larger and older literature base consisting primarily of non-comparative studies concluding that teenage onset indicates a poor outcome. Our results indicate that adolescent-onset and adult-onset psychosis have similar prognostic trajectories, although both may predict a qualitatively different course from childhood-onset psychosis.

Long-term follow-up of the TIPS early detection in psychosis study: effects on 10-year outcome.

OBJECTIVE: Early detection in first-episode psychosis confers advantages for negative, cognitive, and depressive symptoms after 1, 2, and 5 years, but longitudinal effects are unknown. The authors investigated the differences in symptoms and recovery after 10 years between regional health care sectors with and without a comprehensive program for the early detection of psychosis. METHOD: The authors evaluated 281 patients (early detection, N=141) 18 to 65 years old with a first episode of nonaffective psychosis between 1997 and 2001. Of these, 101 patients in the early-detection area and 73 patients in the usual-detection area were followed up at 10 years, and the authors compared their symptoms and recovery. RESULTS: A significantly higher percentage of early-detection patients had recovered at the 10-year follow-up relative to usual-detection patients. This held true despite more severely ill patients dropping out of the study in the usual-detection area. Except for higher levels of excitative symptoms in the early-detection area, there were no symptom differences between the groups. Early-detection recovery rates were higher largely because of higher employment rates for patients in this group. CONCLUSIONS: Early detection of first-episode psychosis appears to increase the chances of milder deficits and superior functioning. The mechanisms by which this strategy improves the long-term prognosis of psychosis remain speculative. Nevertheless, our findings over 10 years may indicate that a prognostic link exists between the timing of intervention and outcome that deserves additional study.