Prediction of clinically significant recurrence after partial nephrectomy. Data from the Cancer Registry of Norway with more than five years of follow-up.

OBJECTIVE: To determine recurrence incidence after partial nephrectomy (PN) for renal cell carcinoma and identify predictors for local recurrence (LR) and metastasis. MATERIAL AND METHODS: We retrospectively evaluated a cohort of 524 patients from the Cancer Registry of Norway, who underwent PN between January 2014 and December 2015 and were followed-up for >6 years. Patient demographics and pathological characteristics were correlated with recurrence and progression-free survival using Kaplan-Meier and Cox regression analyses. RESULTS: Median patient age was 64 years, and the median tumour size was 2.6 cm. A positive surgical margin (PSM) was observed in 11% of the cases, while the LR and metastasis rates were 3.4% and 3.2%, respectively. PSM (hazard ratio [HR], 55.4; 95% confidence interval [CI], 12.55-244.6), tumour number (HR, 45.4; 95% CI, 6.5-316.1) and stage (HR, 33.5; 95% CI, 5.4-205.3) were independent predictors for LR. Undetermined margin status was also a risk factor for LR. Tumour stage (HR, 41.05; 95% CI, 8.52-197.76), tumour necrosis (HR, 1.3; 95% CI, 0.4-4.31) and age (HR, 1.07; 95% CI, 1.01-1.14) were predictors for metastasis. CONCLUSIONS: Both local and distant recurrences after PN were rare, and the pT stage was a common predictor. PSM or indeterminate surgical margin and tumour number were LR predictors, while age at surgery and the presence of tumour necrosis predicted metastasis.

Prevalence of psychological distress in nurses, physicians and leaders working in intensive care units during the COVID-19 pandemic: a national one-year follow-up study.

OBJECTIVE: To report and compare psychological distress as symptoms of anxiety, depression and post-traumatic stress among intensive care units' (ICU) nurses, physicians and leaders at 12 months after the baseline survey (spring 2020), during the COVID-19 pandemic in Norway. Furthermore, to analyse which baseline demographic and COVID ICU-related factors have a significant impact on psychological distress at 12 months. DESIGN: Prospective, longitudinal, observational cohort study. SETTING: Nationwide, 27 of 28 hospitals with COVID ICUs in Norway. PARTICIPANTS: Nurses, physicians and their leaders. At 12 month follow-up 287 (59.3%) of 484 baseline participants responded. PRIMARY AND SECONDARY OUTCOME MEASURES: Symptoms of anxiety and depression using the Hopkins Symptoms Checklist-10 (HSCL-10). Symptoms of post-traumatic stress using the post-traumatic stress disease checklist for the Diagnostic and Statistical Manual of Mental Disorders 5 (PCL-5).Demographics (included previous symptoms of anxiety and depression) and COVID ICU-related factors (professional preparations, emotional experience and support) impacting distress at 12 months. RESULTS: Psychological distress, defined as caseness on either or both HSCL-10 and PCL-5, did not change significantly and was present for 13.6% of the participants at baseline and 13.2% at 12 month follow-up. Nurses reported significantly higher levels of psychological distress than physicians and leaders. Adjusted for demographics and the COVID ICU-related factors at baseline, previous symptoms of depression and fear of infection were significantly associated with higher levels of anxiety and depression at 12 months. Previous symptoms of depression, fear of infection and feeling of loneliness was significantly associated with more symptoms of post-traumatic stress. CONCLUSION: One year into the COVID-19 pandemic 13.2% of the ICUs professionals reported psychological distress, more frequently among the nurses. Fear of infection, loneliness and previous symptoms of depression reported at baseline were associated with higher levels of distress. Protective equipment and peer support are recommended to mitigate distress. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov. Identifier: NCT04372056.

Inhibition of Intimal Thickening By PRH (Proline-Rich Homeodomain) in Mice.

BACKGROUND: Late vein graft failure is caused by intimal thickening resulting from endothelial cell (EC) damage and inflammation which promotes vascular smooth muscle cell (VSMC) dedifferentiation, migration, and proliferation. Nonphosphorylatable PRH (proline-rich homeodomain) S163C:S177C offers enhanced stability and sustained antimitotic effect. Therefore, we investigated whether adenovirus-delivered PRH S163C:S177C protein attenuates intimal thickening via VSMC phenotype modification without detrimental effects on ECs. METHODS: PRH S163C:S177C was expressed in vitro (human saphenous vein-VSMCs and human saphenous vein-ECs) and in vivo (ligated mouse carotid arteries) by adenoviruses. Proliferation, migration, and apoptosis were quantified and phenotype was assessed using Western blotting for contractile filament proteins and collagen gel contraction. EC inflammation was quantified using VCAM (vascular cell adhesion protein)-1, ICAM (intercellular adhesion molecule)-1, interleukin-6, and monocyte chemotactic factor-1 measurement and monocyte adhesion. Next Generation Sequencing was utilized to identify novel downstream mediators of PRH action and these and intimal thickening were investigated in vivo. RESULTS: PRH S163C:S177C inhibited proliferation, migration, and apoptosis and promoted contractile phenotype (enhanced contractile filament proteins and collagen gel contraction) compared with virus control in human saphenous vein-VSMCs. PRH S163C:S177C expression in human saphenous vein-ECs significantly reduced apoptosis, without affecting cell proliferation and migration, while reducing TNF (tumor necrosis factor)-α-induced VCAM-1 and ICAM-1 and monocyte adhesion and suppressing interleukin-6 and monocyte chemotactic factor-1 protein levels. PRH S163C:S177C expression in ligated murine carotid arteries significantly impaired carotid artery ligation-induced neointimal proliferation and thickening without reducing endothelial coverage. Next Generation Sequencing revealed STAT-1 (signal transducer and activator of transcription 1) and HDAC-9 (histone deacetylase 9) as mediators of PRH action and was supported by in vitro and in vivo analyses. CONCLUSIONS: We observed PRH S163C:S177C attenuated VSMC proliferation, and migration and enhanced VSMC differentiation at least in part via STAT-1 and HDAC-9 signaling while promoting endothelial repair and anti-inflammatory properties. These findings highlight the potential for PRH S163C:S177C to preserve endothelial function whilst suppressing intimal thickening, and reducing late vein graft failure.

Monitoring Cellular Proliferation, Migration, and Apoptosis Associated with Atherosclerosis Plaques In Vitro.

Bromodeoxyuridine/5-bromo-2'-deoxyuridine (BrdU) is a nucleoside analog of thymidine and its incorporation into DNA during replication within S-phase of the cell cycle is used to quantify cell proliferation. Quantification of incorporated BrdU is considered the most direct measure of cell proliferation, and here we describe BrdU incorporation into cultured vascular smooth muscle cells (VSMCs) and endothelial cells in vitro. Incorporation of fluorescent-labeled ethynyldeoxyuridine/5-ethynyl-2'-deoxyuridine (EdU) is a novel alternative to BrdU assays and presents significant advantages. This method of detection of EdU based on a simple "click" chemical reaction, which covalently bonds EdU to a fluorescent dye is also outlined in this chapter with a protocol for quantitative analysis of EdU incorporation using a Fiji-based macro. We also describe how proliferation can be assessed by quantification of classical proliferative markers such as phopsho-Ser807/811 retinoblastoma (Rb), proliferating cell nuclear antigen (PCNA) and cyclin D1 by Western blotting. As these markers are involved in different aspects of the cell cycle regulation, examining their expression levels can not only reveal the relative population of proliferating cells but can also improve our understanding of the mechanism of action of a given treatment or intervention. The scratch wound assay is a simple and cost-effective technique to quantify cell migration. A protocol which involves creating a wound in a cell cultured monolayer and measuring the distance migrated by the cells after a predefined time period is also described. Gap creation can also be achieved via physical cell exclusion where cells are seeded in distinct reservoirs of a cell culture insert which reveal a gap upon removal. Cell migration may then be quantified by monitoring the rate of gap closure. The presence of cleaved caspase-3 is a marker of programmed cell death (apoptosis). To detect cleaved caspase-3 in vitro, immunocytochemistry and fluorescence can be performed as outlined in this chapter.

Satisfaction with maternity care among recent migrants: an interview questionnaire-based study.

OBJECTIVE: To examine factors associated with recently migrated women's satisfaction with maternity care in urban Oslo, Norway. DESIGN: An interview-based cross-sectional study, using a modified version of Migrant Friendly Maternity Care Questionnaire. SETTING: Face-to-face interview after birth in two maternity wards in urban Oslo, Norway, from January 2019 to February 2020. PARTICIPANTS: International migrant women, ≤5 years length of residency in Norway, giving birth in urban Oslo, excluding women born in high-income countries. PRIMARY OUTCOME: Dissatisfaction of care during pregnancy and birth, measured using a Likert scale, grouped into satisfied and dissatisfied, in relation to socio-demographic/clinical characteristics and healthcare experiences. SECONDARY OUTCOME: Negative healthcare experiences and their association with reason for migration. RESULTS: A total of 401 women answered the questionnaire (87.6% response rate). Overall satisfaction with maternal healthcare was high. However, having a Norwegian partner, higher education and high Norwegian language comprehension were associated with greater odds of being dissatisfied with care. One-third of all women did not understand the information provided by the healthcare personnel during maternity care. More women with refugee background felt treated differently because of factors such as religion, language and skin colour, than women who migrated due to family reunification. CONCLUSIONS: Although the overall satisfaction was high, for certain healthcare experiences such as understanding information, we found more negative responses. The negative healthcare experiences and factors associated with satisfaction identified in this study have implications for health system planning, education of healthcare personnel and strategies for quality improvement.

Iatrogenic withdrawal syndrome frequently occurs in paediatric intensive care without algorithm for tapering of analgosedation.

BACKGROUND: Analgesics and sedatives are key elements to reduce physiological and psychological stress associated with treatment in paediatric intensive care. Prolonged drug use may induce tolerance and development of iatrogenic withdrawal syndrome (IWS) during the tapering phase. Our primary aim was to describe the prevalence of IWS among critically ill ventilated patients in two Norwegian paediatric intensive care units (PICUs), and secondary to investigate what motivated bedside nurses to administer additional drug doses. METHODS: Mechanically ventilated patients (n = 40) from newborn to eighteen years of age, with continuous infusions of opioids and benzodiazepines for 5 days or more, were included consecutively from May 2016 to June 2018. By using Withdrawal Assessment Tool-1 (WAT-1) twice daily we recorded the prevalence of IWS. Additionally, we recorded signs and symptoms that led bedside nurses to administration extra bolus medication. RESULTS: Peak WAT-1 score indicated an IWS prevalence of 95% in this selected group. The first days of the tapering phase were most critical for IWS. The most frequent symptoms triggering administration of additional bolus doses were agitation/restlessness, and thiopental and propofol were the bolus drugs used most frequently. CONCLUSIONS: IWS affected 95% of the children having received infusions of opioids and benzodiazepines for 5 days or more in PICUs without a tapering protocol for these drugs. This calls for implementation and testing of such weaning protocols.

The association of urine markers of iodine intake with development and growth among children in rural Uganda: a secondary analysis of a randomised education trial.

OBJECTIVE: We examined associations of urine iodide excretion, proxy for iodine intake, with child development and growth. DESIGN: This is a secondary analysis of a 1:1 cluster-randomised trial with a 6-month nutrition/stimulation/hygiene education intervention among mothers of children aged 6-8 months to improve child development and growth. Development was assessed using Bayley Scales of Infant and Toddler Development-III (BSID-III) and Ages and Stages Questionnaire (ASQ), whereas anthropometry was used to assess growth. Urine iodide concentration (UIC) and urine iodide/creatinine ratio (ICR) were measured. SETTING: The current study was conducted in southern Uganda. PARTICIPANTS: We randomly selected 155 children from the 511 enrolled into the original trial and analysed data when they were aged 20-24 and 36 months. RESULTS: Median UIC for both study groups at 20-24 and 36 months were similar (P > 0·05) and within the normal range of 100-199 µg/l (0·79-1·60 µmol/l), whereas the intervention group had significantly higher ICR at 20-24 months. The BSID-III cognitive score was positively associated (P = 0·028) with ICR at 20-24 months in the intervention group. The ASQ gross motor score was negatively associated (P = 0·020) with ICR at 20-24 months among the controls. ICR was not significantly associated with anthropometry in the two study groups at either time-point. CONCLUSIONS: Following the intervention, a positive association was noted between ICR and child's cognitive score at 20-24 months, whereas no positive association with ICR and growth was detected. Iodine sufficiency may be important for child's cognitive development in this setting.

Development of locally relevant clinical guidelines for procedure-related neonatal analgesic practice in Kenya: a systematic review and meta-analysis.

Background Increasing numbers of neonates are undergoing painful procedures in low-income and middle-income countries, with adequate analgesia seldom used. In collaboration with a multi-disciplinary team in Kenya, we aimed to establish the first evidence-based guidelines for the management of routine procedure-related neonatal pain that consider low-resource hospital settings. METHODS: We did a systematic review by searching MEDLINE, Embase, CINAHL, and CENTRAL databases for studies published from Jan 1, 1953, to March 31, 2019. We included data from randomised controlled trials using heart rate, oxygen saturation (SpO2), premature infant pain profile (PIPP) score, neonatal infant pain scale (NIPS) score, neonatal facial coding system score, and douleur aiguë du nouveau-né scale score as pain outcome measures. We excluded studies in which neonates were undergoing circumcision or were intubated, studies from which data were unextractable, or when pain was scored by non-trained individuals. We did a narrative synthesis of all studies, and meta-analysis when data were available from multiple studies comparing the same analgesics and controls and using the same outcome measures. 17 Kenyan health-care professionals formed our clinical guideline development panel, and we used the Grading of Recommendations, Assessment, Development and Evaluation framework and the panel's knowledge of the local health-care context to guide the guideline development process. This study is registered with PROSPERO, CRD42019126620. FINDINGS: Of 2782 studies assessed for eligibility, data from 149 (5%) were analysed, with 80 (3%) of these further contributing to our meta-analysis. We found a high level of certainty for the superiority of breastfeeding over placebo or no intervention (standardised mean differences [SMDs] were -1·40 [95% CI -1·96 to -0·84] in PIPP score and -2·20 [-2·91 to -1·48] in NIPS score), and the superiority of oral sugar solutions over placebo or no intervention (SMDs were -0·38 [-0·61 to -0·16] in heart rate and 0·23 [0·04 to 0·42] in SpO2). We found a moderate level of certainty for the superiority for expressed breastmilk over placebo or no intervention (SMDs were -0·46 [95% CI -0·87 to -0·05] in heart rate and 0·48 [0·20 to 0·75] in SpO2). Therefore, the panel recommended that breastfeeding should be given as first-line analgesic treatment, initiated at least 2 min pre-procedure. Given contextual factors, for neonates who are unable to breastfeed, 1-2 mL of expressed breastmilk should be given as first-line analgesic, or 1-2 mL of oral sugar (≥10% concentration) as second-line analgesic. The panel also recommended parental presence during procedures with adjunctive provision of skin-to-skin care, or non-nutritive sucking when possible. INTERPRETATION: We have generated Kenya's first neonatal analgesic guidelines for routine procedures, which have been adopted by the Kenyan Ministry of Health, and have shown a framework for clinical guideline development that is applicable to other low-income and middle-income health-care settings. FUNDING: Wellcome Trust Research Programme, and the Africa-Oxford Initiative.

Women's satisfaction with midwife-led continuity of care: an observational study in Palestine.

OBJECTIVES: A midwife-led continuity model of care had been implemented in the Palestinian governmental health system to improve maternal services in several rural areas. This study investigated if the model influenced women's satisfaction with care, during antenatal, intrapartum and postnatal period. DESIGN: An observational case-control design was used to compare the midwife-led continuity model of care with regular maternity care. PARTICIPANTS AND SETTING: Women with singleton pregnancies, who had registered for antenatal care at a rural governmental clinic in the West Bank, were between 1 to 6 months after birth invited to answer a questionnaire rating satisfaction with care in 7-point Likert scales. PRIMARY OUTCOME: The mean sum-score of satisfaction with care through the continuum of antenatal, intrapartum and postnatal period, where mean sum-scores range from 1 (lowest) to 7 (highest). SECONDARY OUTCOME: Exclusive breastfeeding. RESULTS: Two hundred women answered the questionnaire, 100 who received the midwife-led model and 100 who received regular care. The median time point of interview were 16 weeks postpartum in both groups. The midwife-led model was associated with a statistically significant higher satisfaction with care during antenatal, intrapartum and postnatal period, with a mean sum-score of 5.2 versus 4.8 in the group receiving regular care. The adjusted mean difference between the groups' sum-score of satisfaction with care was 0.6 (95% CI 0.35 to 0.85), p<0.0001. A statistically significant higher proportion of women who received the midwife-led continuity model of care were still exclusively breastfeeding at the time point of interview, 67% versus 46% in the group receiving regular care, an adjusted OR of 2.56 (1.35 to 4.88) p=0.004. CONCLUSIONS: There is an association between receiving midwife-led continuity of care and increased satisfaction with care through the continuum of pregnancy, intrapartum and postpartum period, and an increased duration of exclusive breastfeeding. TRIAL REGISTRATION NUMBER: NCT03863600.

Child development, growth and microbiota: follow-up of a randomized education trial in Uganda.

BACKGROUND: Undernutrition impairs child development outcomes and growth. In this follow-up study of an open cluster-randomized intervention trial we examined the effects of an education package delivered to mothers in rural Uganda on their children's development, growth and gut microbiota at 36 months of age. METHODS: The parental trial included 511 mother-child pairs recruited when the children were 6-8 months. In that trial, a nutrition, stimulation and hygiene education was delivered to mothers in the intervention group while the control group received routine health care. A follow-up sample of 155 pairs (intervention n = 77, control n = 78) were re-enrolled when the children were 24 months. Developmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development (BSID-III) composite scores for cognitive (primary endpoint), language and motor development. Development outcomes were also evaluated using the Ages and Stages Questionnaire (ASQ) and the Mullen Scales of Early Learning (MSEL). Other outcomes included growth and gut microbiota composition. RESULTS: The demographic characteristics were not different (P > 0.05) between the intervention and control groups and similar to those of the parental study. The intervention group had higher BSID-III scores than controls, with mean difference 10.13 (95% confidence interval (CI): 3.31-17.05, P = 0.002); 7.59 (1.62-13.66, P = 0.01); 9.00 (2.92-15.40, P = 0.005), for cognitive, language and motor composite scores, respectively. An improvement in the intervention compared to the control group was obtained for both the ASQ and the MSEL scores. The mean difference in height-for-age z-score was higher in the intervention compared to the control group: 0.50 (0.25-0.75, P = 0.0001). Gut microbiota composition did not differ significantly between the two study groups. CONCLUSIONS: The maternal education intervention had positive effects on child development and growth at three years, but did not alter gut microbiota composition. This intervention may be applicable in other low-resource settings. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT02098031.

Long term effectiveness of dialectical behavior therapy versus enhanced usual care for adolescents with self-harming and suicidal behavior.

BACKGROUND: Knowledge is lacking on the long-term outcomes of treatment for adolescents with repetitive suicidal and self-harming behavior. Furthermore, the pathways through which treatment effects may operate are poorly understood. Our aims were to investigate enduring treatment effects of dialectical behavior therapy adapted for adolescents (DBT-A) compared to enhanced usual care (EUC) through a prospective 3-year follow-up and to analyze possible mediators of treatment effects. METHODS: Interview and self-report data covering the follow-up interval were collected from 92% of the adolescents who participated in the original randomized trial. TRIAL REGISTRATION NUMBER: NCT01593202 (www.ClinicalTrials.gov). RESULTS: At the 3-year follow-up DBT-A remained superior to EUC in reducing the frequency of self-harm, whereas for suicidal ideation, hopelessness and depressive and borderline symptoms and global level of functioning there were no inter-group differences, with no sign of symptom relapse in either of the participant groups. A substantial proportion (70.8%) of the effect of DBT-A on self-harm frequency over the long-term was mediated through a reduction in participants' experience of hopelessness during the trial treatment phase. Receiving more than 3 months follow-up treatment after completion of the trial treatment was associated with further enhanced outcomes in patients who had received DBT-A. CONCLUSIONS: There were on average no between-group differences at the 3-year follow-up in clinical outcomes such as suicidal ideation, hopelessness, depressive and borderline symptoms. The significantly and consistently larger long-term reduction in self-harm behavior for adolescents having received DBT-A compared with enhanced usual care, however, suggests that DBT-A may be a favorable treatment alternative for adolescents with repetitive self-harming behavior.

Importance of Syndesmotic Reduction on Clinical Outcome After Syndesmosis Injuries.

OBJECTIVES: To evaluate the relationship between syndesmosis reduction and outcome. DESIGN: Retrospective cohort study. SETTING: One Level 1 and 1 Level 3 Trauma Center. PATIENTS: Ninety-seven patients with syndesmosis injury. INTERVENTION: Stabilization of syndesmosis injury. Open reduction and internal fixation of malleolar fracture, if present. MAIN OUTCOME MEASUREMENTS: Anterior, central, and posterior measures of syndesmosis width on computed tomography scans, Olerud-Molander Ankle score, American Orthopaedic Foot and American Orthopaedic Foot and Ankle Society Ankle-Hindfoot score, and range of motion measurements. RESULTS: Eighty-seven patients completed 2 years of follow-up. The difference in anterior tibiofibular distance (aTFD) between the injured and noninjured ankle postoperatively had a significant effect on the Olerud-Molander Ankle score after 6 weeks [b = -2.6, 95% confidence interval (CI), -4.8 to -0.4; P = 0.02], 1 year (b = -2.7, 95% CI, -4.7 to -0.8; P < 0.001), and 2 years (b = -2.6, 95% CI, -4.6 to -0.6; P = 0.009) and on American Orthopaedic Foot and Ankle Society Ankle-Hindfoot score after 6 weeks (b = -2.2, 95% CI, -3.7 to -0.7; P = 0.004), 1 year (b = -1.7, 95% CI, -3.0 to -0.4; P = 0.04), and 2 years (b = -1.9, 95% CI, -3.2 to -0.5; P = 0.006). The effect of computed tomography measurements on range of motion was inconsistent. Receiver operating characteristic (ROC) curves demonstrated that aTFD had adequate discriminatory performance (area under the ROC curve ≥ 0.7) 1 and 2 years after surgery and the central measurement at only 2 years after surgery. ROC analyses indicate a cutoff value for syndesmosis malreduction of 2 mm. The postoperative rate of malreduction was 32%. CONCLUSIONS: The aTFD correlated with clinical outcome. A 2-mm difference in aTFD seems to predict poorer clinical outcome. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Laser technology in the ART laboratory: a narrative review.

To improve success rates, assisted reproductive technology (ART) procedures continually undergo optimization and enhancement such that the best quality gametes and embryos can be identified and manipulated, thus improving clinical outcomes. Laser technology is now being applied across ART to reduce procedure times and increase the consistency and reproducibility of traditional ART techniques such as assisted hatching, embryo biopsy, intracytoplasmic sperm injection cryopreservation and sperm immobilization/selection. This review examines the current status of cutting-edge laser-assisted reproductive technologies, investigates experimental techniques that are increasingly being applied clinically. It highlights the benefits of lasers as a powerful technology at the forefront of both diagnostic and therapeutic treatments for general subfertility and male-factor infertility. However, it is important to note that although lasers are becoming increasingly commonplace in ART units, there is comparatively little information in the existing literature pertaining to the potential negative effects that laser application might have on the developing human embryo, thus creating the need for further investigative research.

Nutrition, hygiene, and stimulation education to improve growth, cognitive, language, and motor development among infants in Uganda: A cluster-randomized trial.

Stunting is associated with impaired cognitive and motor function. The effect of an education intervention including nutrition, stimulation, sanitation, and hygiene on child growth and cognitive/language/motor development, delivered to impoverished mothers in Uganda, was assessed. In a community-based, open cluster-randomized trial, 511 mother/children dyads aged 6-8 months were enrolled to an intervention (n = 263) or control (n = 248) group. The primary outcome was change in length-for-age z-score at age 20-24 months. Secondary outcomes included anthropometry and scores on the 2 developmental scales: Bayley Scales of Infant and Toddler Development-III and the Ages and Stages Questionnaire. There was no evidence of a difference in mean length-for-age z-score at 20-24 months between the 2 study groups: 0.10, 95% CI [-0.17, 0.36], p = .49. The intervention group had higher mean composite development scores than the controls on Bayley Scales of Infant and Toddler Development-III, the mean difference being 15.6, 95% CI [10.9, 20.2], p = .0001; 9.9, 95% CI [6.4, 13.2], p = .0001; and 14.6, 95% CI [10.9, 18.2], p = .0001, for cognitive, language, and motor composite scores, respectively. The mean difference in scores from the Ages and Stages Questionnaire were 7.0, 95% CI [2.9, 11.3], p = .001; 5.9, 95% CI [1.2, 10.3], p = .01; 4.2, 95% CI [1.7, 6.7], p = .001; 8.9, 95% CI [5.3, 12.3], p = .0001; and 4.4, 95% CI [0.0, 8.8], p = .05, for communication, gross motor, fine motor, problem solving, and personal-social development, respectively. The intervention education delivered to mothers promoted early development domains in cognitive, language, and motor development but not linear growth of small children in impoverished rural communities in Uganda. Our study showed that child development may be improved with a relatively low cost intervention strategy. This trial was registered at ClinicalTrials.gov as NCT02098031.

The impact of borderline personality disorder and sub-threshold borderline personality disorder on the course of self-reported and clinician-rated depression in self-harming adolescents.

BACKGROUND: Studies on adults suggest that the presence of comorbid depression and Borderline Personality Disorder (BPD) is associated with an elevated risk of self-harming behaviours and that self-harming behaviours, when present, will have higher severity. This comorbidity, furthermore, complicates clinical assessments, which may be an obstacle to early identification and proper intervention. Adolescents who self-harm frequently report high levels of depressive symptoms, but this is often not reflected in the clinicians' assessment. BPD is still a controversial diagnosis in young people, and less is known about the clinical significance of comorbid BPD in adolescent populations.The purpose of the present study was to examine the impact of BPD on the assessment and course of self-reported and clinician-rated depression in self-harming adolescents before and after a treatment period of 19 weeks. We hypothesized that, compared to adolescents without BPD, adolescents with BPD would self-report higher levels of depression at baseline, and that they would have less reduction in depressive symptoms. METHODS: A total of 39 adolescents with depressive disorders and BPD-traits participating in a randomised controlled trial on treatment of self-harm with Dialectical Behaviour Therapy adapted for Adolescents or enhanced usual care were included. Adolescents with full-syndrome BPD (n = 10) were compared with adolescents with sub-threshold BPD (n = 29) with respect to their self-reported and clinician-rated depressive symptoms, suicidal ideation and global level of functioning at baseline, and after 19 weeks of treatment (end of trial period). RESULTS: At baseline, adolescents with full-syndrome BPD self-reported significantly higher levels of depressive symptoms and suicidal ideation compared to adolescents with sub-threshold BPD, whereas the two groups were rated as equally depressed by the clinicians. At trial completion, all participants had a significant reduction in suicidal ideation, however, adolescents with BPD had a poorer treatment outcome in terms of significantly higher levels of clinician-rated and self-reported depressive symptoms and significantly lower levels of global functioning. At baseline as well as at trial completion, self-reported and clinician-rated levels of depressive symptoms were not significantly correlated in adolescents with BPD. In a multiple linear regression analysis, a diagnosis of BPD and a high baseline level of clinician-rated depressive symptoms predicted higher levels of depressive symptoms at trial completion, whereas receiving Dialectical Behaviour Therapy predicted lower levels of depressive symptoms. CONCLUSION: Our findings suggest that a diagnosis of BPD may have a strong impact on the assessment and course of depressive symptoms in self-harming adolescents. Although rated as equally depressed, adolescents with BPD self-reported significantly higher levels of depressive symptoms and suicidal ideation at baseline, and showed a poorer outcome in terms of higher levels of depressive symptoms and lower levels of global functioning at trial completion compared to adolescents with sub-threshold BPD. Our findings suggest that receiving Dialectical Behaviour Therapy could lead to a greater reduction in depressive symptoms, although firm conclusions cannot be drawn given the limited sample size.Clinicians should be aware of the possibility of underestimating the severity of depression in the context of emotional and behavioral dysregulation. Providing BPD specific treatments seems to be important to achieve sufficient treatment response with regard to depressive symptoms in adolescents with BPD-traits. TRIAL REGISTRATION: Treatment for Adolescents With Deliberate Self Harm; NCT00675129, registered May 2008.

Phenolic Compounds from the Lichen Lobaria orientalis.

The chemical investigation of the EtOAc extract of Lobaria orientalis collected in the southwestern part of Central Vietnam led to the isolation of new ß-orcinol depsidones, lobarientalones A and B (1 and 2), and diphenyl ethers, lobariethers A-E (3-7). These types of structures are often reported in different lichen species, but the absolute configuration of the stereogenic acetal center has not been defined. This is the first assessment of the (1S) absolute configuration of the stereogenic acetal center using electronic circular dichroism (ECD) spectroscopic data and by comparison with the ECD data of analogous compounds. Based on the co-occurrence of the depsidones, 1,10-di-O-methylstictic acid (8) and (1-2), and diphenyl ethers (3-7), a plausible biosynthesis route toward 1-8 is proposed.

Methionine and methionine sulfoxide treatment induces M1/classical macrophage polarization and modulates oxidative stress and purinergic signaling parameters.

Methionine is an essential amino acid involved in critical metabolic process, and regulation of methionine flux through metabolism is important to supply this amino acid for cell needs. Elevation in plasma methionine commonly occurs due to mutations in methionine-metabolizing enzymes, such as methionine adenosyltransferase. Hypermethioninemic patients exhibit clinical manifestations, including neuronal and liver disorders involving inflammation and tissue injury, which pathophysiology is not completely established. Here, we hypothesize that alterations in macrophage inflammatory response may contribute to deleterious effects of hypermethioninemia. To this end, macrophage primary cultures were exposed to methionine (1 mM) and/or its metabolite methionine sulfoxide (0.5 mM), and M1/proinflammatory or M2/anti-inflammatory macrophage polarization was evaluated. In addition, inflammation-related pathways including oxidative stress parameters, as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities; reactive oxygen species (ROS) production, and purinergic signaling, as ATP/ADP/AMPase activities, were investigated. Methionine and/or methionine sulfoxide induced M1/classical macrophage activation, which is related to proinflammatory responses characterized by increased iNOS activity and TNF-α release. Further experiments showed that treatments promoted alterations on redox state of macrophages by differentially modulated SOD and CAT activities and ROS levels. Finally, methionine and/or methionine sulfoxide treatment also altered the extracellular nucleotide metabolism, promoting an increase of ATPase/ADPase activities in macrophages. In conclusion, these findings contribute to better understand the participation of proinflammatory responses in cell injury observed in hypermethioninemic patients.

Development of a laser-activated mesoporous silica nanocarrier delivery system for applications in molecular and genetic research.

Nanoparticles have revolutionized medical research over the last decade. One notable emerging area of nanomedicine is research developments in the reproductive sciences. Since increasing evidence indicates links between abnormal gene expression and previously unexplained states of infertility, there is a strong impetus to develop tools, such as nanoparticle platforms, to elucidate the pathophysiological mechanisms underlying such states. Mesoporous silica nanoparticles (MSNPs) represent a powerful and safe delivery tool for molecular and genetic investigations. Nevertheless, ongoing progress is restricted by low efficiency and unpredictable control of cargo delivery. Here, we describe for the first time, the development of a laser-activated MSNP system with heat-responsive cargo. Data derived from human embryonic kidney cells (HEK293T) indicate that when driven by a heat-shock promoter, MSNP cargo exhibits a significantly increased expression following infrared laser stimulus to stimulate a heat-shock response, without adverse cytotoxic effects. This delivery platform, with increased efficiency and the ability to impart spatial and temporal control, is highly useful for molecular and genetic investigations. We envision that this straightforward stimuli-responsive system could play a significant role in developing efficient nanodevices for research applications, for example in reproductive medicine.

Molecular mechanisms of membrane interaction at implantation.

Successful pregnancy is dependent upon the implantation of a competent embryo into a receptive endometrium. Despite major advancement in our understanding of reproductive medicine over the last few decades, implantation failure still occurs in both normal pregnancies and those created artificially by assisted reproductive technology (ART). Consequently, there is significant interest in elucidating the etiology of implantation failure. The complex multistep process of implantation begins when the developing embryo first makes contact with the plasma membrane of epithelial cells within the uterine environment. However, although this biological interaction marks the beginning of a fundamental developmental process, our knowledge of the intricate physiological and molecular processes involved remains sparse. In this synopsis, we aim to provide an overview of our current understanding of the morphological changes which occur to the plasma membrane of the uterine endothelium, and the molecular mechanisms that control communication between the early embryo and the endometrium during implantation. A multitude of molecular factors have been implicated in this complex process, including endometrial integrins, extracellular matrix molecules, adhesion molecules, growth factors, and ion channels. We also explore the development of in vitro models for embryo implantation to help researchers investigate mechanisms which may underlie implantation failure. Understanding the precise molecular pathways associated with implantation failure could help us to generate new prognostic/diagnostic biomarkers, and may identify novel therapeutic targets.

Dialectical Behavior Therapy Compared With Enhanced Usual Care for Adolescents With Repeated Suicidal and Self-Harming Behavior: Outcomes Over a One-Year Follow-Up.

OBJECTIVE: We conducted a 1-year prospective follow-up study of posttreatment clinical outcomes in adolescents with recent and repetitive self-harm who had been randomly allocated to receive 19 weeks of either dialectical behavior therapy adapted for adolescents (DBT-A) or enhanced usual care (EUC) at community child and adolescent psychiatric outpatient clinics. METHOD: Assessments of self-harm, suicidal ideation, depression, hopelessness, borderline symptoms, and global level of functioning were made at the end of the 19-week treatment period and at follow-up 1 year later. Altogether 75 of the 77 (97%) adolescents participated at both time points. Frequencies of hospitalizations, emergency department visits and other use of mental health care during the 1-year follow-up period were recorded. Change analyses were performed using mixed effects linear spline regression and mixed effect Poisson regression with robust variance. RESULTS: Over the 52-week follow-up period, DBT-A remained superior to EUC in reducing the frequency of self-harm. For other outcomes such as suicidal ideation, hopelessness, and depressive or borderline symptoms and for the global level of functioning, inter-group differences apparent at the 19-week assessment were no longer observed, mainly due to participants in the EUC group having significantly improved on these dimensions over the follow-up year, whereas DBT-A participants remained unchanged. CONCLUSION: A stronger long-term reduction in self-harm and a more rapid recovery in suicidal ideation, depression, and borderline symptoms suggest that DBT-A may be a favorable treatment alternative for adolescents with repetitive self-harming behavior. CLINICAL TRIAL REGISTRATION INFORMATION: Treatment for Adolescents With Deliberate Self Harm; http://clinicaltrials.gov/; NCT00675129.