The Horyzons project: a randomized controlled trial of a novel online social therapy to maintain treatment effects from specialist first‐episode psychosis services

This study aimed to determine whether, following two years of specialized support for first‐episode psychosis, the addition of a new digital intervention (Horyzons) to treatment as usual (TAU) for 18 months was more effective than 18 months of TAU alone. We conducted a single‐blind randomized controlled trial. Participants were people with first‐episode psychosis (N=170), aged 16‐27 years, in clinical remission and nearing discharge from a specialized service. They were randomly assigned (1:1) to receive Horyzons plus TAU (N=86) or TAU alone (N=84) between October 2013 and January 2017. Horyzons is a novel, comprehensive digital platform merging: peer‐to‐peer social networking; theory‐driven and evidence‐informed therapeutic interventions targeting social functioning, vocational recovery and relapse prevention; expert clinician and vocational support; and peer support and moderation. TAU involved transfer to primary or tertiary community mental health services. The primary outcome was social functioning at 18 months as measured by the Personal and Social Performance Scale (PSP). Forty‐seven participants (55.5%) in the Horyzons plus TAU group logged on for at least 6 months, and 40 (47.0%) for at least 9 months. Social functioning remained high and stable in both groups from baseline to 18‐month follow‐up, with no evidence of significant between‐group differences (PSP mean difference: –0.29, 95% CI: –4.20 to 3.63, p=0.77). Participants in the Horyzons group had a 5.5 times greater increase in their odds to find employment or enroll in education compared with those in TAU (odds ratio, OR=5.55, 95% CI: 1.09‐28.23, p=0.04), with evidence of a dose‐response effect. Moreover, participants in TAU were twice as likely to visit emergency services compared to those in the Horyzons group (39% vs. 19%; OR=0.31, 95% CI: 0.11‐0.86, p=0.03, number needed to treat, NNT=5). There was a non‐significant trend for lower hospitalizations due to psychosis in the Horyzons group vs. TAU (13% vs. 27%; OR=0.36, 95% CI: 0.11‐1.08, p=0.07, NNT=7). So, although we did not find a significant effect of Horyzons on social functioning compared with TAU, the intervention was effective in improving vocational or educational attainment, a core component of social recovery, and in reducing usage of hospital emergency services, a key aim of specialized first‐episode psychosis services. Horyzons holds significant promise as an engaging and sustainable intervention to provide effective vocational and relapse prevention support for young people with first‐episode psychosis beyond specialist services.     

Comparing three‐year extension of early intervention service to regular care following two years of early intervention service in first‐episode psychosis: a randomized single blind clinical trial

This study aimed to determine if, following two years of early intervention service for first‐episode psychosis, three‐year extension of that service was superior to three years of regular care. We conducted a randomized single blind clinical trial using an urn randomization balanced for gender and substance abuse. Participants were recruited from early intervention service clinics in Montreal. Patients (N=220), 18‐35 years old, were randomized to an extension of early intervention service (EEIS; N=110) or to regular care (N=110). EEIS included case management, family intervention, cognitive behaviour therapy and crisis intervention, while regular care involved transfer to primary (community health and social services and family physicians) or secondary care (psychiatric outpatient clinics). Cumulative length of positive and negative symptom remission was the primary outcome measure. EEIS patients had a significantly longer mean length of remission of positive symptoms (92.5 vs. 63.6 weeks, t=4.47, p<0.001), negative symptoms (73.4 vs. 59.6 weeks, t=2.84, p=0.005) and both positive and negative symptoms (66.5 vs. 56.7 weeks, t=2.25, p=0.03) compared to regular care patients. EEIS patients stayed in treatment longer than regular care patients (mean 131.7 vs. 105.3 weeks, t=3.98, p<0.001 through contact with physicians; 134.8 ± 37.7 vs. 89.8 ± 55.2, t=6.45, p<0.0001 through contact with other health care providers) and received more units of treatment (mean 74.9 vs. 39.9, t=4.21, p<0.001 from physicians, and 57.3 vs. 28.2, t=4.08, p<0.001 from other health care professionals). Length of treatment had an independent effect on the length of remission of positive symptoms (t=2.62, p=0.009), while number of units of treatment by any health care provider had an effect on length of remission of negative symptoms (t=?2.70, p=0.008) as well as total symptoms (t=?2.40, p=0.02). Post‐hoc analysis showed that patients randomized to primary care, based on their better clinical profile at randomization, maintained their better outcome, especially as to remission of negative symptoms, at the end of the study. These data suggest that extending early intervention service for three additional years has a positive impact on length of remission of positive and negative symptoms compared to regular care. This may have policy implications for extending early intervention services beyond the current two years.     

A network meta‐analysis of the effects of psychotherapies,pharmacotherapies and their combination in the treatment of adult depression

No network meta‐analysis has examined the relative effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression, while this is a very important clinical issue. We conducted systematic searches in bibliographical databases to identify randomized trials in which a psychotherapy and a pharmacotherapy for the acute or long‐term treatment of depression were compared with each other, or in which the combination of a psychotherapy and a pharmacotherapy was compared with either one alone. The main outcome was treatment response (50% improvement between baseline and endpoint). Remission and acceptability (defined as study drop‐out for any reason) were also examined. Possible moderators that were assessed included chronic and treatment‐resistant depression and baseline severity of depression. Data were pooled as relative risk (RR) using a random‐effects model. A total of 101 studies with 11,910 patients were included. Depression in most studies was moderate to severe. In the network meta‐analysis, combined treatment was more effective than psychotherapy alone (RR=1.27; 95% CI: 1.14‐1.39) and pharmacotherapy alone (RR=1.25; 95% CI: 1.14‐1.37) in achieving response at the end of treatment. No significant difference was found between psychotherapy alone and pharmacotherapy alone (RR=0.99; 95% CI: 0.92‐1.08). Similar results were found for remission. Combined treatment (RR=1.23; 95% CI: 1.05‐1.45) and psychotherapy alone (RR=1.17; 95% CI: 1.02‐1.32) were more acceptable than pharmacotherapy. Results were similar for chronic and treatment‐resistant depression. The combination of psychotherapy and pharmacotherapy seems to be the best choice for patients with moderate depression. More research is needed on long‐term effects of treatments (including cost‐effectiveness), on the impact of specific pharmacological and non‐pharmacological approaches, and on the effects in specific populations of patients.     

Two‐year Follow‐up in 21,784 Overweight Children and Adolescents With Lifestyle Intervention

Although randomized controlled trials demonstrated the long‐term efficacy of lifestyle interventions in overweight children, the effects of these interventions in clinical practice under real‐life conditions are largely unknown. One hundred twenty‐nine centers specialized in outpatient pediatric obesity care participated in this quality assessment. All patients presenting before the year 2006 for lifestyle intervention of at least 6 months duration in these institutions were analyzed in a 2‐year follow‐up. A total of 21,784 (45% male) overweight children and adolescents aged 2–20 years (mean BMI 30.4 kg/m², mean SDS‐BMI 2.51, mean age 12.6 years) were included in the analysis. Based on an intention‐to‐treat analysis with variables set back to baseline in lost of follow‐up, 22% of the children reduced their SDS‐BMI after 6 months, 15% after 12 months, and 7% after 24 months, but only in 24, 17, and 8% of children, respectively, complete data were available. In the five treatment centers with the best outcome (518 patients), 83% of the children reduced their overweight after 6 months, 67% after 12 months, and 51% after 24 months. Under real‐life conditions, most treatment centers cannot prove the long‐term efficacy of their interventions due to high drop‐out rate or lack of documentation. Conversely, some institutions achieved a reduction of overweight in nearly the half of their patients 24 months after baseline demonstrating the great heterogeneity in outcome. To improve the effectiveness of lifestyle interventions in real‐life studying, the process and structure quality as well as their long‐term results is urgently needed.     

Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second‐generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first‐generation antipsychotics, FGAs). As some reports questioned this notion, we meta‐analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head‐to‐head RCTs, including 32 FGA and 86 SGA arms, were meta‐analyzed, yielding 32 FGA‐SGA pairs and 35 SGA‐SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3‐7.8%) vs. 2.6% (95% CI: 2.0‐3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39‐0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28‐0.45, p<0.0001, number‐needed‐to‐treat, NNT=20). Meta‐regression showed no FGA dose effect on FGA‐SGA comparisons (Z=?1.03, p=0.30). FGA‐SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non‐clozapine SGAs in exploratory pairwise comparisons. SGA‐SGA comparisons confirmed the olanzapine advantage vs. non‐clozapine SGAs (RaR=0.66, 95% CI: 0.49‐0.88, p=0.006, k=17, NNT=100). This meta‐analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.     

Long‐term cytological and histological outcomes in women managed with loop excision treatment under local anaesthetic for high‐grade cervical intraepithelial neoplasia

Y. L. Woo, C. Badley, E. Jackson and R. Crawford Long‐term cytological and histological outcomes in women managed with loop excision treatment under local anaesthetic for high‐grade cervical intraepithelial neoplasia Objective: This study examines the impact of excision margin status after large loop excision of the transformation zone (LLETZ) under local anaesthetic for high‐grade cervical intraepithelial neoplasia (HG‐CIN) on the cytological and histological outcomes up to 5 years after treatment. Methods: Prospective cytological and histological data were obtained by examination of the colposcopy database at Addenbrooke’s Hospital, Cambridge, UK. All women aged between 19 and 50 years who underwent treatment for HG‐CIN by LLETZ under local anaesthetic were included in the study. Patients without follow‐up data were excluded from the study. The excision margin status was correlated with the subsequent cytological and histological outcomes. Results: A series of 967 women with CIN2 and CIN3 underwent LLETZ excision under local anaesthetic. Overall, 42% of women had disease present at the excision margin following LLETZ. Women with CIN3 were more likely than those with CIN2 to have an involved excision margin (P < 0.0001). Cytological recurrence was highest at 12 months (16%) and did not correlate with the CIN grade or excision margin status. Histological recurrence/persistence was also highest at 12 months follow‐up (15%) and this correlated with grade of CIN and margin status (P < 0.0001). Conclusions: Histological recurrence/persistence correlates with grade of CIN and excision margin status. Management of HG‐CIN in an outpatient setting under local anaesthetic is safe, cost effective and yields a favourable long‐term outcome.     

Validation of the new DSM‐5‐TR criteria for prolonged grief disorder and the PG‐13‐Revised (PG‐13‐R) scale

Although the concept of pathological grief dates back at least as far as Freud’s “Mourning and Melancholia”, there has been opposition to its recognition as a distinct mental disorder. Resistance has been overcome by evidence demonstrating that distinctive symptoms of prolonged grief disorder (PGD) – an attachment disturbance featuring yearning for the deceased, loss of meaning and identity disruption – can endure, prove distressing and disabling, and require targeted treatment. In acknowledgement of this evidence, the American Psychiatric Association Assembly has recently voted to include PGD as a new mental disorder in the DSM‐5‐TR. We tested the validity of the new DSM criteria for PGD and of an adapted version of our PG‐13 scale, the PG‐13‐Revised (PG‐13‐R), designed to map onto these criteria, using data from investigations conducted at Yale University (N=270), Utrecht University (N=163) and Oxford University (N=239). Baseline assessments were performed at 12‐24 months post‐loss; follow‐up assessments took place 5.3‐12.0 months later. Results indicated that the PG‐13‐R grief symptoms represent a unidimensional construct, with high degrees of internal consistency (Cronbach's alpha = 0.83, 0.90 and 0.93, for Yale, Utrecht and Oxford, respectively). The DSM PGD diagnosis was distinct from post‐traumatic stress disorder (phi=0.12), major depressive disorder (phi=0.25) and generalized anxiety disorder (phi=0.26) at baseline. Temporal stability was remarkable for this diagnosis (r=0.86, p<0.001). Kappa agreement between a PG‐13‐R threshold symptom summary score of 30 and the DSM symptom criterion for PGD was 0.70‐0.89 across the datasets. Both the DSM PGD diagnosis and the PG‐13‐R symptom summary score at baseline were significantly associated (p<0.05) with symptoms and diagnoses of major depressive disorder, post‐traumatic stress disorder and/or generalized anxiety disorder, suicidal ideation, worse quality of life and functional impairments at baseline and at follow‐up, in the Yale, Utrecht and Oxford datasets. Overall, the DSM‐5‐TR criteria for PGD and the PG‐13‐R both proved reliable and valid measures for the classification of bereaved individuals with maladaptive grief responses.     

Thieno[3,2‐b][1]benzothiophene Derivative as a New π‐Bridge Unit in D–π–A Structural Organic Sensitizers with Over 10.47% Efficiency for Dye‐Sensitized Solar Cells

Three new thieno[3,2‐b][1]benzothiophene ( TBT )‐based donor–π–acceptor (D–π–A) sensitizers, coded as SGT ‐ 121 , SGT ‐ 129 , and SGT ‐ 130 , have been designed and synthesized for dye‐sensitized solar cells (DSSCs), for the first time. The TBT , prepared by fusing thiophene unit with the phenyl unit of triphenylamine donor, is utilized as the π‐bridge for all sensitizers with good planarity. They have been molecularly engineered to regulate the highest occupied molecular orbital (HOMO)‐lowest unoccupied molecular orbital (LUMO) energy levels and extend absorption range as well as to control the electron‐transfer process that can ensure efficient dye regeneration and prevent undesired electron recombination. The photovoltaic performance of SGT‐sensitizer‐based DSSCs employing Co(bpy)₃^2+/3+ (bpy = 2,2′‐bipyridine) redox couple is systematically evaluated in a thorough comparison with Y123 as a reference sensitizer. Among them, SGT ‐ 130 with benzothiadiazole‐phenyl ( BTD ‐ P ) unit as an auxiliary acceptor exhibits the highest power‐conversion efficiency (PCE) of 10.47% with J_sc = 16.77 mA cm^?2, V_oc = 851 mV, and FF = 73.34%, whose PCE is much higher than that of Y123 (9.5%). It is demonstrated that the molecular combination of each fragment in D–π–A organic sensitizers can be a pivotal factor for achieving the higher PCEs and an innovative strategy for strengthening the drawbacks of the π‐bridge.     

Residual FDG‐PET metabolic activity in metastatic melanoma patients with prolonged response to anti‐PD‐1 therapy

18‐Fluorodeoxyglucose positron emission tomography (FDG‐PET) scans were performed on 27 patients with unresectable stage IIIC or IV melanoma after prolonged treatment with anti‐PD‐1 antibodies to examine the hypothesis that patients with prolonged response to treatment may have metabolically inactive lesions by FDG‐PET. Scans were performed at a median of 15.2 months (range 12–29 months) after starting treatment. Overall, 15 of 27 (56%) patients had a positive FDG‐PET scan. Eight patients with positive scans underwent biopsy; 5 of 8 (62%) were melanoma and 3 of 8 (38%) were immune cell infiltrates. Of the 12 patients with negative FDG‐PET scans, six had residual computerized tomography‐visible lesions, five have ceased treatment, and none have recurred with follow‐up of 6–10 months. Patients with residual metastases after a prolonged period without progression on anti‐PD‐1 therapy may have metabolically inactive lesions. Isolated metabolically active lesions in clinically well patients may reveal immune cell infiltrates rather than melanoma.     

Triblock‐Terpolymer‐Directed Self‐Assembly of Mesoporous TiO2: High‐Performance Photoanodes for Solid‐State Dye‐Sensitized Solar Cells

A new self‐assembly platform for the fast and straightforward synthesis of bicontinuous, mesoporous TiO₂ films is presented, based on the triblock terpolymer poly(isoprene ‐ b ‐ styrene ‐ b ‐ ethylene oxide). This new materials route allows the co‐assembly of the metal oxide as a fully interconnected minority phase, which results in a highly porous photoanode with strong advantages over the state‐of‐the‐art nanoparticle‐based photoanodes employed in solid‐state dye‐sensitized solar cells. Devices fabricated through this triblock terpolymer route exhibit a high availability of sub‐bandgap states distributed in a narrow and low enough energy band, which maximizes photoinduced charge generation from a state‐of‐the‐art organic dye, C220. As a consequence, the co‐assembled mesoporous metal oxide system outperformed the conventional nanoparticle‐based electrodes fabricated and tested under the same conditions, exhibiting solar power‐conversion efficiencies of over 5%.     

A therapeutic application of the experience sampling method in the treatment of depression: a randomized controlled trial

In depression, the ability to experience daily life positive affect predicts recovery and reduces relapse rates. Interventions based on the experience sampling method (ESM-I) are ideally suited to provide insight in personal, contextualized patterns of positive affect. The aim of this study was to examine whether add-on ESM-derived feedback on personalized patterns of positive affect is feasible and useful to patients, and results in a reduction of depressive symptomatology. Depressed outpatients (n=102) receiving pharmacological treatment participated in a randomized controlled trial with three arms: an experimental group receiving add-on ESM-derived feedback, a pseudo-experimental group participating in ESM but receiving no feedback, and a control group. The experimental group participated in an ESM procedure (three days per week over a 6-week period) using a palmtop. This group received weekly standardized feedback on personalized patterns of positive affect. Hamilton Depression Rating Scale – 17 (HDRS) and Inventory of Depressive Symptoms (IDS) scores were obtained before and after the intervention. During a 6-month follow-up period, five HDRS and IDS assessments were completed. Add-on ESM-derived feedback resulted in a significant and clinically relevant stronger decrease in HDRS score relative to the control group (p<0.01; −5.5 point reduction in HDRS at 6 months). Compared to the pseudo-experimental group, a clinically relevant decrease in HDRS score was apparent at 6 months (B=−3.6, p=0.053). Self-reported depressive complaints (IDS) yielded the same pattern over time. The use of ESM-I was deemed acceptable and the provided feedback easy to understand. Patients attempted to apply suggestions from ESM-derived feedback to daily life. These data suggest that the efficacy of traditional passive pharmacological approach to treatment of major depression can be enhanced by using person-tailored daily life information regarding positive affect.     

Co‐expression of NF‐κB‐p65 and phosphorylated NF‐κB‐p105 is associated with poor prognosis in surgically resectable non‐small cell lung cancer

Nuclear factor‐kappa B (NF‐κB) as a prognostic marker remains unclear in non‐small cell lung cancer (NSCLC). Here, we studied NF‐κB‐p65 (p65) expression and phosphorylated NF‐κB‐p105 (p‐p105) expression in NSCLC and correlated the finding with overall survival (OS) and clinicopathological features. A total of 186 archival samples from patients with surgically resectable NSCLC were probed with p65 and p‐p105 (Ser 932). The p65‐positive expression and p‐p105‐positive expression were defined as distinct nuclear p65 and cytoplasmic p‐p105 labelling in at least 1% of tumour cells, respectively. The positive staining of p65 alone, p‐p105 alone and co‐expression of p65 and p‐p105 were observed in 61 (32.8%), 90 (48.4%) and 35 (18.8%) patients, respectively. Co‐expression of p65 and p‐p105 but not of either p65 or p‐p105 alone was associated with a poor prognosis. Patients with co‐expression of p65 and p‐p105 had a shorter OS than others, median OS 26.5 months versus 64.1 months, HR 1.85 (95% CI: 1.18–2.91), P = 0.007. There was no statistically significant association between clinicopathological characteristics and either p65 or p‐p105 alone or co‐expression of p65 and p‐p105. This indicates that co‐expression of p65 and p‐p105 was a poor prognostic factor, and pathologic studies of NF‐κB expression could include multiple pathway components in NSCLC.     

A randomized controlled effectiveness trial of cognitive behavior therapy for post-traumatic stress disorder in terrorist-affected people in Thailand

Although cognitive behaviour therapy (CBT) is the treatment of choice for post-traumatic stress disorder (PTSD), there is no evidence of its success with PTSD patients still under direct threat of terrorist attacks. This study reports the first randomized controlled trial of CBT for PTSD terrorist-affected people. Twenty-eight survivors of terrorist attacks in southern Thailand were randomized to 8 sessions of either CBT or treatment as usual (TAU). CBT was modified to accommodate the realistic threats facing patients. There were independent assessments conducted before, immediately after, and 3 months following treatment. Main outcome measures included symptoms of PTSD (PTSD Symptom Scale Interview), depression (Beck Depression Inventory) and complicated grief (Inventory of Complicated Grief). CBT resulted in significantly greater reduction in symptoms, including PTSD, depression, and complicated grief, at follow-up than TAU. Relative to TAU, CBT had stronger effect sizes at follow-up for PTSD, depression, and complicated grief. More patients in the CBT condition (75%) achieved high end-state functioning than participants in the TAU (33%). This preliminary evidence suggests that PTSD, depression, and complicated grief can be effectively treated despite ongoing threats of terrorism. Further, it demonstrates that non-specialist mental health workers in a non-western setting can be efficiently trained in using CBT, and this training can translate into successful treatment gains in trauma-affected individuals.     

The efficacy of smartphone‐based mental health interventions for depressive symptoms: a meta‐analysis of randomized controlled trials

The rapid advances and adoption of smartphone technology presents a novel opportunity for delivering mental health interventions on a population scale. Despite multi‐sector investment along with wide‐scale advertising and availability to the general population, the evidence supporting the use of smartphone apps in the treatment of depression has not been empirically evaluated. Thus, we conducted the first meta‐analysis of smartphone apps for depressive symptoms. An electronic database search in May 2017 identified 18 eligible randomized controlled trials of 22 smartphone apps, with outcome data from 3,414 participants. Depressive symptoms were reduced significantly more from smartphone apps than control conditions (g=0.38, 95% CI: 0.24‐0.52, p<0.001), with no evidence of publication bias. Smartphone interventions had a moderate positive effect in comparison to inactive controls (g=0.56, 95% CI: 0.38‐0.74), but only a small effect in comparison to active control conditions (g=0.22, 95% CI: 0.10‐0.33). Effects from smartphone‐only interventions were greater than from interventions which incorporated other human/computerized aspects along the smartphone component, although the difference was not statistically significant. The studies of cognitive training apps had a significantly smaller effect size on depression outcomes (p=0.004) than those of apps focusing on mental health. The use of mood monitoring softwares, or interventions based on cognitive behavioral therapy, or apps incorporating aspects of mindfulness training, did not affect significantly study effect sizes. Overall, these results indicate that smartphone devices are a promising self‐management tool for depression. Future research should aim to distil which aspects of these technologies produce beneficial effects, and for which populations.     

The relationship of C‐reactive protein to obesity‐related depressive symptoms: A longitudinal study

Objective:

Obesity has been shown to produce a state of systematic low‐grade inflammation that may have detrimental neuropsychiatric effects.

Design and Methods:

Longitudinal associations between obesity, inflammation, and depressive symptoms amongst a cohort of older English adults over 4 years of follow‐up were examined. Participants were 3,891 obese and nonobese people drawn from the English longitudinal study of ageing (ELSA) [aged 64.9 (SD = 8.8) years, 44.6% men]. Depressive symptoms were assessed at baseline and after 4 years of follow‐up using the eight‐item center for epidemiological studies—depression scale (CES‐D).

Results:

Approximately 26.3% (N = 1,025) of the sample were categorized as obese at baseline. Obesity at baseline was associated with elevated levels of depressive symptoms at follow‐up (P < 0.001), in analyses that adjusted for depression levels at baseline and sociodemographic and background variables including the prevalence of permanent illness/disability, alcohol consumption, sedentary behavior, and smoking. In addition, C‐reactive protein (CRP) concentrations at baseline were independently associated with CES‐D depression scores at follow‐up (P = 0.008) in fully adjusted analyses. Subsequent mediation analyses revealed that CRP levels explained ～20% of the obesity‐related longitudinal change in depression scores.

Conclusion:

These data suggest that chronic inflammation may be a key determinant of depressive symptoms in obesity.     

p16INK4a/Ki‐67 dual labelling as a marker for the presence of high‐grade cancer cells or disease progression in urinary cytopathology

E. Piaton, A. S. Advenier, C. Carré, M. Decaussin‐Petrucci, F. Mege‐Lechevallier and A. Ruffion
p16 ^INK4a /Ki‐67 dual labelling as a marker for the presence of high‐grade cancer cells or disease progression in urinary cytopathology Objective: Overexpression of p16^INK4a independent of the presence of E6–E7 oncoproteins of high‐risk papillomaviruses has been identified in bladder carcinoma in situ lesions with or without concurrent papillary or invasive high‐grade (HG) urothelial carcinoma. As p16^INK4a and Ki‐67 co‐expression clearly indicates deregulation of the cell cycle, the aim of this study was to investigate the frequency of p16^INK4a/Ki‐67 dual labelling in urinary cytology samples. Methods: Immunolabelling was performed in demounted, destained Papanicolaou slides after ThinPrep^® processing. A total of 84 urinary cytology samples (18 negative, 10 low grade, 19 atypical urothelial cells and 37 high grade) were analysed for p16^INK4a/Ki‐67 co‐expression. We assessed underlying urothelial malignancy with cystoscopy, histopathology and follow‐up data in every case. Results: Compared with raw histopathological results, p16 ^INK4a/Ki‐67 dual labelling was observed in 48 out of 55 (87.3%) HG lesions and in 11 out of 29 (37.9%) negative, papillary urothelial neoplasia of low malignant potential or low‐grade carcinomas (P = 0.05). All cases with high‐grade/malignant cytology were dual labelled. Sixteen out of 17 (94.1%) carcinoma in situ cases and eight out of 14 (57.1%) cases with atypical urothelial cells matching with HG lesions were dual labelled. Extended follow‐up allowed three cases of progression to be diagnosed in dual‐labelled cases with negative/low‐grade cytology results after a 9‐ to 11‐months delay. Conclusions: The data show that p16^INK4a/Ki‐67 co‐expression allows most HG cancer cells to be detected initially and in the follow‐up period. Additional studies are needed in order to determine whether dual labelling can be used as a triage tool for atypical urothelial cells in the urine.     

Predictors for self‐directed aggression in Italian prisoners include externalizing behaviors,childhood trauma and the serotonin transporter gene polymorphism 5‐HTTLPR

Suicidal behavior and self‐mutilation can be regarded as the expression of self‐directed aggression and both are common in prison populations. We investigated the influence of externalizing behaviors, depressive symptoms, childhood trauma, 5‐HTTLPR variants on self‐directed aggression (N = 145) in a group of 702 male Italian prisoners. Participants were comprehensively evaluated, including for psychiatric disorders, impulsive traits, lifetime aggressive behavior [Brown‐Goodwin Lifetime History of Aggression (BGHA)], hostility, violent behavior during incarceration, depressive symptomatology [Hamilton Depression Rating Scale (HDRS)], childhood trauma [Childhood Trauma Questionnaire (CTQ)]. Logistic regression analysis showed false discovery rate corrected independent main effects of externalizing behaviors: BGHA (P = 0.001), violent behavior in jail (P = 0.007), extraversion (P = 0.015); HDRS (P = 0.0004), Axis I disorders (P = 0.015), CTQ (P = 0.004) and 5‐HTTLPR genotype (P = 0.02). Carriers of 5‐HTTLPR high (L_AL_A), intermediate (L_AL_G, SL_A) activity variants were more likely to have exhibited self‐directed aggression relative to the low activity (L_GL_G, SL_G, SS) variant: high/low: odds ratio (OR) = 2.3, 95% confidence interval (CI) 1.27–4.68, P = 0.007; intermediate/low: OR = 1.96, 95% CI 1.09–3.68, P = 0.025. The CTQ main effect was driven by physical abuse. There was no interactive effect of 5‐HTTLPR and CTQ. Secondary logistic regression analyses in (1) all suicide attempters (N = 88) and (2) all self‐mutilators (N = 104), compared with controls showed that in both groups, childhood trauma (P = 0.008–0.01), depression (P = 0.0004–0.001) were strong predictors. BGHA, violent behavior in jail predicted self‐mutilation (P = 0.002) but not suicide attempts (P = 0.1). This study was able to distinguish differing influences on self‐directed aggression between groups of closely related predictor variables within the externalizing behavioral domain. 5‐HTTLPR had an independent, variant dosage effect.     

Long‐Term Weight Development in Women: A 15‐Year Follow‐up of the Effects of Pregnancy

Objective: The aim of this study was to evaluate how well prepregnancy BMI, gestational weight gain, and postpartum weight retention predict retention of weight 15 years later among parous women. Research Methods and Procedures: The Stockholm Pregnancy and Women's Nutrition (SPAWN) study is a long‐term follow‐up study of women who delivered children in 1984 to 1985 (n = 2342). The participants initially filled out questionnaires about their eating and exercise habits, social circumstances, etc. before, during, and at 1 year after pregnancy. Anthropometric data were also sampled. Fifteen years later, these women were invited to take part in the follow‐up study. Anthropometric measurements were collected, and similar questions were asked. Five hundred sixty‐three women participated in the SPAWN 15‐year follow‐up study. The sample was divided into groups to examine three presumably critical time periods: 1) overweight and normal weight before pregnancy; 2) low, intermediate, and high weight gainers during pregnancy; and 3) low, intermediate, and high weight retainers at 1 year after pregnancy. Results: The overweight women did not gain more weight during pregnancy or retain more weight at 1 year follow‐up. High weight gainers during pregnancy retained more weight at the 1‐year and the 15‐year follow‐ups. High weight retainers had gained more during pregnancy and retained it at the 15‐year follow‐up. Fifty‐six percent of the high weight gainers during pregnancy ended up in the high weight retainers group. Discussion: Women who are overweight before pregnancy do not have a higher risk of postpartum weight retention than normal weight women. Thus, it is not necessarily the initially overweight woman who should be the target or focus of weight control programs during or after pregnancy. Both high weight gainers and high weight retainers had higher BMI at the 15‐year follow‐up, although only 56% of the high weight gainers during pregnancy were also classified as high weight retainers at the 1‐year follow‐up. Weight retention at the end of the postpartum year predicts future overweight 15 years later.     

Sex Hormones and Sexual Function in Obese Men Losing Weight

Objective: To study the impact of a weight‐loss program on sex hormones and sexual function among 38 middle‐aged obese men (BMI ≥35 kg/m²). Research Methods and Procedures: A randomized controlled clinical trial was conducted. The treatment group (n = 19) participated in a 4‐month weight‐loss program including 10 weeks on a very‐low‐energy diet (VLED) and 17 behavior modification visits. There was no intervention in the control group (n = 19). Both groups were followed for 8 months, i.e., 22 weeks after the active weight loss in the treatment group. The outcome measures (weight, sex hormones, sexual function, leptin, and metabolic variables) were obtained at baseline and at three time‐points during follow‐up. Results: The mean weight loss in the treatment group was 21 kg at the end of the 10‐week VLED. At the end of follow‐up, the maintained weight loss was 17 kg of baseline weight. The control group was weight stable throughout the study. In the treatment group, increases in sex hormone‐binding globulin, testosterone, and high‐density lipoprotein‐cholesterol, as well as decreases in insulin and leptin, were maintained until the end of follow‐up, although with VLED, the level of several hormones and metabolic variables improved transiently during the rapid weight loss. There were no significant changes in the questionnaire scores on sexual function in either group. Discussion: We conclude that obese men lose weight and increase their serum testosterone level on a weight‐loss program with VLED and behavior modification. However, they do not change their sexual function scores.     

Association between polymorphisms in the promoter region of miR‐17‐92 cluster and systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association of genetic polymorphisms in the promoter region of miR‐17‐92 with systemic lupus erythematosus (SLE). The gene polymorphism was analysed using SNaPshot in 312 SLE patients and 396 controls. Relative expression of miR‐17‐92 was measured by quantitative real‐time PCR. Association was found between rs9515692 and a decreased risk of SLE (CT vs CC: OR = 0.65, 95%CI, 0.46‐0.92, P = .014; CT+TT vs CC: OR = 0.64, 95%CI, 0.46‐0.90, P = .009; T vs C: OR = 0.69, 95%CI, 0.52‐0.92, P = .010, respectively). Haplotype analysis showed that C‐G‐G, C‐A‐A haplotypes were associated with an increased SLE risk (OR=4.46, 95%CI, 2.17‐9.17, P < 0.001; OR=2.33, 95%CI, 1.44‐3.76, P < 0.001, respectively). T allele and CT+TT genotypes in rs9515692 were associated with decreased risk of anti‐dsDNA in SLE (CT+TT vs CC: OR = 0.42, 95%CI = 0.24‐0.72, P = .002; T vs A: OR = 0.49, 95%CI = 0.31‐0.79, P = .003). Moreover, rs9515692 CT+TT genotypes had a higher level of miR‐17 as compared to CC genotype (P = .017). These findings suggest that the rs9515692 CT+TT genotypes were a protective factor for the susceptibility of SLE, probably by increasing the expression of miR‐17.